Multimodal evoked potentials measure and predict disability progression in early relapsing-remitting multiple sclerosis.

In 37 patients with early relapsing-remitting multiple sclerosis (RRMS), a multimodal EP score (mEPS) and clinical scores (Expanded Disability Status Scale (EDSS) and multiple sclerosis functional composite (MSFC)) were obtained prospectively over 24 months. Changes in mEPS correlated with changes in EDSS (Spearman's rho = 0.69, p < 0.0001) and MSFC (rho = -0.41, p < 0.02). Patients with relevant EDSS progression (n = 7) showed stronger mEPS deterioration than clinically stable patients (10.8 +/- 3.2 versus 1.3 +/- 0.8, p < 0.005). Baseline mEPS was not significantly correlated with baseline EDSS but with EDSS after 24 months (rho = 0.39, p < 0.02). The data suggest that serial mEPS measure and moderately predict clinically relevant disease activity in the therapeutically most relevant early stage of RRMS.

Electroencephalographic signatures of attentional and cognitive default modes in spontaneous brain activity fluctuations at rest.

We assessed the relation between hemodynamic and electrical indices of brain function by performing simultaneous functional MRI (fMRI) and electroencephalography (EEG) in awake subjects at rest with eyes closed. Spontaneous power fluctuations of electrical rhythms were determined for multiple discrete frequency bands, and associated fMRI signal modulations were mapped on a voxel-by-voxel basis. There was little positive correlation of localized brain activity with alpha power (8-12 Hz), but strong and widespread negative correlation in lateral frontal and parietal cortices that are known to support attentional processes. Power in a 17-23 Hz range of beta activity was positively correlated with activity in retrosplenial, temporo-parietal, and dorsomedial prefrontal cortices. This set of areas has previously been characterized by high but coupled metabolism and blood flow at rest that decrease whenever subjects engage in explicit perception or action. The distributed patterns of fMRI activity that were correlated with power in different EEG bands overlapped strongly with those of functional connectivity, i.e., intrinsic covariations of regional activity at rest. This result indicates that, during resting wakefulness, and hence the absence of a task, these areas constitute separable and dynamic functional networks, and that activity in these networks is associated with distinct EEG signatures. Taken together with studies that have explicitly characterized the response properties of these distributed cortical systems, our findings may suggest that alpha oscillations signal a neural baseline with "inattention" whereas beta rhythms index spontaneous cognitive operations during conscious rest.

EEG-correlated fMRI of human alpha activity.

Electroencephalography-correlated functional magnetic resonance imaging (EEG/fMRI) can be used to identify blood oxygen level-dependent (BOLD) signal changes associated with both physiological and pathological EEG events. Here, we implemented continuous and simultaneous EEG/fMRI to identify BOLD signal changes related to spontaneous power fluctuations in the alpha rhythm (8-12 Hz), the dominant EEG pattern during relaxed wakefulness. Thirty-two channels of EEG were recorded in 10 subjects during eyes-closed rest inside a 1.5-T magnet resonance (MR) scanner using an MR-compatible EEG recording system. Functional scanning by echoplanar imaging covered almost the entire cerebrum every 4 s. Off-line MRI artifact subtraction software was applied to obtain continuous EEG data during fMRI acquisition. The average alpha power over 1-s epochs was derived at several electrode positions using a Fast Fourier Transform. The power time course was then convolved with a canonical hemodynamic response function, down-sampled, and used for statistical parametric mapping of associated signal changes in the image time series. At all electrode positions studied, a strong negative correlation of parietal and frontal cortical activity with alpha power was found. Conversely, only sparse and nonsystematic positive correlation was detected. The relevance of these findings is discussed in view of the current theories on the generation and significance of the alpha rhythm and the related functional neuroimaging findings.

H(2)O(2) mediates oxidative stress-induced epidermal growth factor receptor phosphorylation.

We used a well-established thiol-alkylating agent, N-ethylmaleimide (NEM), to oxidatively stress human keratinocytes. Time course studies revealed that NEM rapidly depleted keratinocytes of reduced glutathione (GSH), which was followed by rapidly increasing levels of intracellular reactive oxygen species (ROS) and subsequently by phosphorylation of epidermal growth factor receptor (EGFR). Pretreatment with antioxidants or enhanced catalase activity in keratinocytes inhibited ROS/H(2)O(2) accumulation and EGFR phosphorylation, demonstrating that H(2)O(2) production is a mediator required for EGFR phosphorylation. Collectively, these results suggest a sequence of events leading to EGFR phosphorylation which is likely shared by oxidative stress-inducing agents, namely: (1) GSH depletion; (2) H(2)O(2) accumulation; and (3) EGFR phosphorylation. We propose that depletion of GSH and accumulation of H(2)O(2) are upstream events and critical mediators required for ligand-independent phosphorylation of growth factor receptors in response to oxidative stress.

Vitamin E analog modulates UVB-induced signaling pathway activation and enhances cell survival.

We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinases 1 and 2 (ERK1/2) and p38 signaling pathways via reactive oxygen species, an effect that can be modulated by antioxidants. Trolox, a water-soluble vitamin E analog, is among the antioxidants that are currently being investigated for their preventive and protective potential against harmful effects of UV radiation to the skin. We found that Trolox inhibits both basal and UVB-induced intracellular H(2)O(2) generation in primary keratinocytes in a concentration-dependent manner. Trolox did not significantly affect UVB-induced phosphorylation of EGFR. Stronger inhibition was observed for ERK1/2 activation at lower, and for p38 activation at higher, concentrations of Trolox added to cells before exposure to UVB. Similarly different effects were found with regard to length of pretreatment with Trolox before UVB exposure-increasing inhibition for ERK1/2 activation at shorter, and for p38 activation at longer, pretreatment intervals. UVB-induced c-jun-N-terminal kinase activation was potently suppressed by Trolox. Also, increasing the pretreatment time of Trolox decreased the rate of cell death following UVB. In conclusion, UVB-induced signaling pathway activation is differentially modulated by Trolox. Further investigation into the time-dependent biologic activation of Trolox and its metabolic products, and modulation of signal transduction with cell outcome should facilitate development of rational strategies for pharmacologic applications.

UVB-induced epidermal growth factor receptor phosphorylation is critical for downstream signaling and keratinocyte survival.

We have recently shown that UVB radiation activates epidermal growth factor receptor (EGFR)/extracellular regulated kinase 1 and 2 (ERK1/2) and p38 signaling pathways in keratinocytes. However, the functional relevance of these processes for downstream signaling and cell survival remains to be determined. The specific EGFR inhibitor PD153035 markedly decreased UVB-induced phosphorylation of EGFR, ERK1/2 and shc, whereas p38 activation was unaffected. PD153035 pretreatment followed by UVB reduced clonogenic potential and enhanced peroxide production, apoptosis and cell death. Our data suggest that ligand-independent phosphorylation of EGFR and likely dependent downstream signaling pathways regulate cellular defense mechanisms important for cell survival following oxidative stress.

Anti-psoriatic drug anthralin activates JNK via lipid peroxidation: mononuclear cells are more sensitive than keratinocytes.

Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known, however, about differential sensitivities of targeted cell types and specific mechanisms of signaling pathway activation. We demonstrate that anthralin exerts potent effects on keratinocytes and mononuclear cells through strong induction of lipid peroxidation and JNK activation, a stress-induced signal transduction pathway. Lipid peroxidation was observed rapidly and half-maximal levels of lipid peroxidation were reached at a 10-fold lower concentration of anthralin for peripheral blood mononuclear cells vs normal keratinocytes. JNK activation was detected in peripheral blood mononuclear cells at a 40-fold lower anthralin dose compared with keratinocytes. For both cell types, selected inhibitors of lipid peroxidation prevented JNK activation. This study demonstrates that mononuclear leukocytes are markedly more sensitive than keratinocytes to anthralin-induced lipid peroxidation and JNK activation. We identify anthralin as a novel and potent inducer of JNK activation and demonstrate that this process is mediated, at least in part, by lipid peroxidation which is among the earliest and most proximate, membrane-related responses to anthralin yet described.

UVB activates ERK1/2 and p38 signaling pathways via reactive oxygen species in cultured keratinocytes.

We have previously shown that hydrogen peroxide is an important mediator of ultraviolet B induced phosphorylation of the epidermal growth factor receptor in human keratinocytes. Here we demonstrate that physiologic doses of ultraviolet B and hydrogen peroxide stimulate activation of two related but distinct mitogen-activated protein kinase pathways: extracellular regulated kinase 1 and 2 (ERK1/2), as well as p38, the mammalian homolog of HOG1 in yeast which is a major kinase for a recently identified stress-induced signaling pathway. The time-dependent activation of ERK1/2 and p38 are distinct, and ultraviolet B-induced ERK1/2 activation is downregulated more rapidly than p38. Using dihydrorhodamine or Amplex as specific fluorescent dye probes, we show that ultraviolet B-induced peroxides can be inhibited by ascorbic acid. Ascorbic acid strongly blocks ERK1/2 and p38 activation by ultraviolet B and hydrogen peroxide whereas pyrrolidine dithiocarbamate and butyl hydroxyanisole are less effective. Pyrrolidine dithiocarbamate was unable to inhibit ultraviolet B-induced p38 activation. Cell death was increased after ultraviolet B when ERK1/2 activation was attenuated by the specific inhibitor PD098059. The distinct time courses and extents of activation and inhibition of ERK1/2 and p38 indicate that these pathways are separate and regulated independently in keratinocytes. Specific types of reactive oxygen species induced by ultraviolet B as well as selective activation or inhibition of specific phosphatases may mediate these responses in keratinocytes. These findings demonstrate that reactive oxygen species are important multifunctional mediators of ultraviolet B-induced ERK1/2 and p38 signaling transduction pathways and suggest that ERK1/2 may play an important part in protecting keratinocytes from cell death following oxidative stress.

H2O2 is required for UVB-induced EGF receptor and downstream signaling pathway activation.

Ultraviolet radiation (UVR)-induced receptor phosphorylation is increasingly recognized as a widely occurring phenomenon. However, the mechanisms, mediators, and sequence of events involved in this process remain ill-defined. We have recently shown that exposure of human keratinocytes to physiologic doses of ultraviolet B radiation (UVB) activates epidermal growth factor receptor (EGFR)/extracellular-regulated kinase 1 and 2 (ERK1/2), and p38 signaling pathways via reactive oxygen species. Here we demonstrate that UVB exposure increased intra- and extracellular H2O2 production rapidly in a time-dependent manner. An EGFR-specific monoclonal antibody abrogated EGFR autophosphorylation and markedly decreased the phosphorylation of ERK1/2 whereas p38 activation was unaffected. Overexpression of catalase strongly inhibited UVB-induced EGFR/ERK1/2 pathway activation. These findings establish the sequence of events after UVB irradiation: (i) H2O2 generation, (ii) EGFR phosphorylation, and (iii) ERK activation. Our results identify UVB-induced H2O2 as a second messenger that is required for EGFR and dependent downstream signaling pathways activation.

H2O2 is an important mediator of UVB-induced EGF-receptor phosphorylation in cultured keratinocytes.

Exposure of human keratinocytes to physiologic doses of ultraviolet B (UVB) radiation induces phosphorylation of the epidermal growth factor receptor (EGFR). We demonstrate that H2O2 generated by UVB mediates EGFR phosphorylation. Using dihydrorhodamine 123 as a specific fluorescent dye probe, we show that UVB irradiation (50-800 J per m2) of keratinocytes leads within minutes to concentration-dependent intracellular production of H2O2. A corresponding concentration-dependent increase in the release of extracellular H2O2 was measured by using Amplex, a derivative of dihydrophenoxazine. The levels of intracellular H2O2 that are induced by UVB irradiation and that stimulate EGFR phosphorylation correlate strongly with the response induced by exogenously added H2O2. UVB or H2O2 demonstrated concentration- and time-dependent stimulation of EGFR phosphorylation that was initially observed within 1-5 min and exhibited a proportionate delay for UVB-induced production of H2O2. EGFR phosphorylation induced by UVB or H2O2 declined significantly toward baseline levels by 4 h and could be restimulated after H2O2 but not after UVB exposure. Phosphorylation of EGFR was inhibited by the structurally unrelated antioxidants butylated hydroxyanisole, N-acetyl-L-cysteine, and pyrrolidine dithiocarbamate, or by the H2O2-degrading enzyme catalase. These data indicate that generation of H2O2 by UVB radiation of human keratinocytes participates in the rapid, ligand-independent phosphorylation of EGFR and implicate H2O2 as a biologic mediator in EGFR activation and regulation of the downstream signaling cascade. UVB-induced H2O2 has the potential to initiate or modulate early EGFR-mediated signaling events that could play an important role in the cellular response to oxidative stress.

Infusions with molsidomine and isosorbide-5-mononitrate in congestive heart failure: mechanisms underlying attenuation of effects.

The use of nitrates for treatment of heart failure is encumbered by tolerance, caused by whatever mechanism, which has been reported only in a few instances with sydnonimines. Accordingly, we compared molsidomine (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to maximal hemodynamic effects, rapidity and extent of attenuation, and underlying mechanisms by means of constant infusions over 24 h each in 15 patients with chronic congestive heart failure (NYHA II-III) with a placebo-controlled, double-blind, randomized, crossover protocol. Hemodynamic measurements and determinations of neurohormones were performed at baseline and at 2, 8, and 24 h after the beginning of infusions. With molsidomine, reductions of diastolic pulmonary artery pressure by 29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus placebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8 h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding times. Increases in renin activity amounted to 130% (p < 0.001), 117% (p < 0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0 (each NS) with the nitrate at the corresponding times. Hematocrit was reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with molsidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate. We conclude that neurohumoral counterregulation or fluid shift, which is even more pronounced with molsidomine despite longer-lasting effects, has no essential role in nitrate-tolerance development. With molsidomine, such a role cannot be ruled out, although alternatively, a fluid shift from arterial to the low-pressure arm of circulation during the later course of infusion would be even more likely.

Clinical comparison of antiischemic efficacy of isosorbide dinitrate and molsidomine.

In 16 patients with documented coronary artery disease, the extent and duration of acute antiischemic and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate once daily and 8 mg of sustained-release molsidomine 3 times daily were compared according to a randomized, double-blind, cross-over and placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST) at an identical workload and determination of plasma concentrations of both substances. Up to 8 h after dosing in the morning, more marked and sustained effects were observed with the nitrate (ST at 2 h, -82%; p < 0.001; at 8 h, -64%; p < 0.01) than with molsidomine (2 h, -68%; p < 0.001; at 8 h, -9%; NS). At 12 h, no more meaningful actions were detectable with isosorbide dinitrate (-13%, NS) despite plasma concentrations still within a range otherwise considered therapeutically effective, whereas with molsidomine, at 4 h after renewed dosing, this parameter was reduced by 38% (p < 0.01). However, therapeutic coverage over a 24-h period could be demonstrated on neither regimen, in the case of the nitrate because of the development of early tolerance, and in the case of molsidomine with its meaningfully shorter half-life because of the necessity of increasing the dosing frequency even further. No meaningful adverse effects were observed with either regimen. Nonresponders, overall a minority on one treatment, responded completely to the alternative regimen and vice versa.

Anti-ischemic effects of first and second dose of 20 mg isosorbide dinitrate administered 5 hours apart: attenuation of effects despite rising plasma concentration.

Based on evidence that there may be early tolerance development even within the first daily cycle of treatment, this study was undertaken to evaluate the duration and extent of the antiischemic effects of two 20 mg doses of isosorbide dinitrate as used in a well-established regimen documented to maintain effectiveness during long-term treatment. Ischemia parameters were analyzed at 2 and 4 1/2 hours after the first dose as well as at 2 and 7 hours after the second dose given 5 hours later. The studies were performed in 10 male patients with documented coronary artery disease using bicycle ergometry and a double-blind, randomized, placebo-controlled, crossover protocol. ST-segment depression was reduced by 59% (p < 0.0005) at 2 hours and by 42% (p < 0.01) at 4 1/2 hours after the first tablet and by 38% (p < 0.005) at 2 hours and by 15% (p < 0.05) at 7 hours after the second tablet. Increments in ischemia-free workload capacity amounted to 112% (p < 0.005) and to 41% (p < 0.05) after the first tablet and 68% (p < 0.05) and 38% (p < 0.05) at 2 and 7 hours after the second tablet. At 2 and 4 1/2 hours after the first tablet, plasma concentrations of isosorbide dinitrate were 8.4 and 5.9 ng/ml, and those of isosorbide-5-mononitrate were 166.6 and 130.3 ng/ml. At 2 and 7 hours after the second tablet, the concentrations of isosorbide dinitrate were 9.1 and 5.9 ng/ml, and those of isosorbide-5-mononitrate were 224.5 and 148.1 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic evaluation of two regimens of molsidomine in patients with chronic congestive heart failure.

We investigated the extent and duration of the haemodynamic effects of two regimens of molsidomine, i.e. two tablets of a standard regimen consisting of 4 mg given 6 h apart and one tablet of 16 mg in sustained-release form once daily in 13 patients with chronic congestive heart failure using a placebo-controlled, randomized, double-blind and crossover protocol over a period of 12 h. Both regimens significantly affected systolic, mean and diastolic pulmonary arterial pressure (reductions of up to 15%), right atrial pressure (reductions of up to 35%) and total pulmonary resistance (reductions of up to 18%). The lower dose achieved its maximum action after about 1 h and remained effective for 2 h, whereas the higher dose in sustained-release form showed maximal efficacy at 2 h and remained active even at 12 h. In contrast, only minor changes in arterial blood pressure, systemic vascular resistance and cardiac output were observed on both regimens, almost exclusively at 2 h. Heart rate was not affected by either of the regimens tested. Neither regimen led to any untoward adverse effects. Thus, molsidomine is a potent vasodilating agent which, apart from its effects on preload, also acts on pulmonary arterial and right atrial pressures, leaving systemic circulation largely unaffected on the regimens tested. Administered on its own, it is therefore suitable for treatment of congestive heart failure.

Pharmacokinetics and additional anti-ischaemic effectiveness of amlodipine, a once-daily calcium antagonist, during acute and long-term therapy of stable angina pectoris in patients pre-treated with a beta-blocker.

Amlodipine 10 mg was evaluated for additional anti-ischaemic and anti-anginal efficacy in 14 patients pre-treated with a beta-blocker who had documented coronary artery disease, stable angina pectoris, and > or = 2 mm of exercise-induced ST segment depression. For 2 days the patients received open-label amlodipine and then, according to a randomized, placebo-controlled, cross-over and double-blind protocol, they were treated with amlodipine or placebo, respectively, once a day for 3 weeks each. Exercise tests and blood sampling for plasma concentrations of amlodipine were performed at 8 and at 24 h after dosing on both days of acute testing as well as on day 18 of chronic treatment. During chronic treatment, when plasma concentrations fluctuated between 23.5 ng.ml-1 at 8 h and 14 ng.ml-1 at 24 h post-dosing, ST segment depression at an individually comparable workload was significantly decreased by 28% compared with placebo (P < 0.005) at both points in time. Increases in ischaemia-free workload capacity amounted to 76% (P < 0.005) and to 81% (P < 0.01) at 8 and at 24 h, respectively. The number of anginal attacks was reduced by 39% (P < 0.05). Conversely, after initial dosing, i.e. when plasma concentrations declined from 4.7 ng.ml-1 to 3.9 ng.ml-1, influences upon ischaemic parameters compared to control values were markedly less at 24 h as opposed to 8 h. There were no untoward side effects observed at any point in time.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effectiveness of various combination therapies in patients with coronary heart disease]. / Effektivität verschiedener Kombinationstherapien bei Patienten mit koronarer Herzerkrankung.

There is only a limited number of studies available comparing the effectiveness of various combinations of anti-ischemic and antianginal substances in the same patients with coronary artery disease and stable angina pectoris and even these are restricted to either only a few drugs or a single point in time for testing. Accordingly, this study was undertaken to determine to what extent the combination of two or three drugs with different anti-ischemic mechanisms of action such as the long-acting form of the beta-blocker metoprolol and isosorbide dinitrate (ISDN) in sustained-release form as well as the calcium channel blockers nisoldipine and diltiazem in sustained-release form, which previously have not been tested in combination, are capable of enhancing effectiveness and prolonging duration of action. In a double-blind, randomized, crossover study in eleven patients with documented coronary artery disease and stable angina pectoris the effects of monotherapy with 200 mg metoprolol in long-acting form were compared with those of combined treatment with 120 mg ISDN sustained-release or 10 mg nisoldipine or 120 mg diltiazem sustained-release as well as ISDN and nisoldipine and finally, ISDN and diltiazem by means of an intraindividual analysis. For assessment of anti-ischemic and antianginal effects, symptom-limited exercise testing was carried out before as well as three, eight, twelve and 24 hours after medication. The parameters analyzed were ST-segment depression at the highest comparable workload, ischemia-free and symptom-free exercise capacity (one minute prior to ST-segment depression of 1 mm or onset of angina pectoris) as well as the systolic blood pressure--heart rate product at the highest comparable workload and at the highest ischemia-free workload, that is one minute prior to an ischemic reaction of 1 mm. Based on the ST-segment depression, all combinations of two drugs (metoprolol and ISDN at three hours; metoprolol and diltiazem at eight hours) led to a significant or at least relative increase of effectiveness. On comparison of the various double combinations, those with nisoldipine showed an early dissipation of action which, twelve hours after administration, was significantly less marked than those with diltiazem. Of the two tested triple combinations, metoprolol, ISDN and diltiazem was either significantly more effective than the various double combinations (metoprolol and ISDN or metoprolol and nisoldipine, both at eight and twelve hours; metoprolol and diltiazem, twelve hours) or relatively more effective and showed clear prolongation of the effects in excess of twelve hours.(ABSTRACT TRUNCATED AT 400 WORDS)

[Treatment of symptomatic and asymptomatic myocardial ischemia using 120 mg delayed-action ISDN]. / Behandlung der symptomatischen und asymptomatischen myokardialen Ischämie mit 120 mg retardiertem ISDN.

Most episodes of myocardial ischemia in patients with coronary artery disease are incurred asymptomatically during everyday physical activities. While the necessity for medical treatment of angina pectoris is clearly established, the indication for treatment of asymptomatic ischemia is based on prevention of structural myocardial damage or malignant arrhythmias and on the implication of improvement in prognosis. In this regard, however, no reliable data is available. Additionally, only relatively few controlled studies have been carried out to investigate the influence of medical treatment on the ischemic episodes. Moreover, on assessment of treatment with Holter monitoring, as opposed to standardized ergometric testing, the substantial spontaneous variability of the frequency of ischemic episodes from day to day must be taken into consideration. Accordingly, in 25 patients with documented coronary artery disease, using a double-blind, randomized, placebo-controlled protocol with two periods of 48 hours of Holter monitoring each, we analyzed the effects of 120 mg isosorbide dinitrate in sustained-release form on the frequency, duration and extent as well as the circadian variation of transient myocardial ischemia during everyday physical activities and differentiated these from the spontaneous day-to-day fluctuations. During the placebo phase, 277 episodes with ST-segment depression greater than 1 mm were detected, 81% of which were asymptomatic. During treatment with 120 mg isosorbide dinitrate in sustained-release form, the number of episodes was reduced significantly (p less than 0.05) to 119 (-57%) where the decrease in symptomatic and asymptomatic episodes of 54% and 58%, respectively, was comparable (Figure 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-acting, marked antiischemic effect maintained unattenuated during long-term interval treatment with once-daily isosorbide-5-mononitrate in sustained-release form.

In 18 patients with documented coronary artery disease, the antiischemic effect of 50 and 100 mg isosorbide-5-mononitrate (IS-5-MN) in sustained-release (SR) form was investigated using a randomized, double-blind, crossover, placebo-controlled protocol. After the initial administration of both dosages, compared to placebo there were significant reductions in exercise-induced ST-segment depression and significant increases in ischemia-free exercise time at all times of testing. At 12 hours, the 100-mg dosage still amounted to greater than 50% of its maximum and was significantly more marked than the 50 mg dose. Accordingly, the 100-mg dosage can be assumed to confer a longer duration of action. At the end of 3 weeks of long-term treatment, the significant antiischemic effects were not diminished versus those observed after initial administration. There was no evidence of tolerance development with either dosage. The IS-5-MN plasma concentration during long-term administration displayed, within the 24-hour treatment cycle, a clear decrease to low baseline values and a marked 5- to 7-fold increase after the daily dose in accordance with the response known to be prerequisite to successful interval treatment. Thus, the once-daily administration of IS-5-MN SR with dosages of 50 mg and, more markedly, 100 mg, provides effective antiischemic protection throughout the daily period of most physical activities in patients with stable angina pectoris.

[Long-term therapy with nitrates. How can continuous effectiveness be achieved?]. / Langzeittherapie mit Nitraten. Wie ist eine anhaltende Effektivität zu gewährleisten?

Due to rapidly occurring tolerance, "continuous" administration of nitrates can no longer be considered justified. The development of tolerance can be avoided and, thus, the antiischemic effect maintained during long-term treatment only by providing a nitrate-free interval. Dosing regimens with documented effectiveness in long-term controlled studies are available for both isosorbide dinitrate and isosorbide 5-mononitrate as well as for transdermal nitroglycerin systems.