Acute engagement of Gq-mediated signaling in the bed nucleus of the stria terminalis induces anxiety-like behavior.

The bed nucleus of the stria terminalis (BNST) is a brain region important for regulating anxiety-related behavior in both humans and rodents. Here we used a chemogenetic strategy to investigate how engagement of G protein-coupled receptor (GPCR) signaling cascades in genetically defined GABAergic BNST neurons modulates anxiety-related behavior and downstream circuit function. We saw that stimulation of vesicular γ-aminobutyric acid (GABA) transporter (VGAT)-expressing BNST neurons using hM3Dq, but neither hM4Di nor rM3Ds designer receptors exclusively activated by a designer drug (DREADD), promotes anxiety-like behavior. Further, we identified that activation of hM3Dq receptors in BNST VGAT neurons can induce a long-term depression-like state of glutamatergic synaptic transmission, indicating DREADD-induced changes in synaptic plasticity. Further, we used DREADD-assisted metabolic mapping to profile brain-wide network activity following activation of Gq-mediated signaling in BNST VGAT neurons and saw increased activity within ventral midbrain structures, including the ventral tegmental area and hindbrain structures such as the locus coeruleus and parabrachial nucleus. These results highlight that Gq-mediated signaling in BNST VGAT neurons can drive downstream network activity that correlates with anxiety-like behavior and points to the importance of identifying endogenous GPCRs within genetically defined cell populations. We next used a microfluidics approach to profile the receptorome of single BNST VGAT neurons. This approach yielded multiple Gq-coupled receptors that are associated with anxiety-like behavior and several potential novel candidates for regulation of anxiety-like behavior. From this, we identified that stimulation of the Gq-coupled receptor 5-HT2CR in the BNST is sufficient to elevate anxiety-like behavior in an acoustic startle task. Together, these results provide a novel profile of receptors within genetically defined BNST VGAT neurons that may serve as therapeutic targets for regulating anxiety states and provide a blueprint for examining how G-protein-mediated signaling in a genetically defined cell type can be used to assess behavior and brain-wide circuit function.

Liposomal amphotericin B in the treatment of visceral leishmaniasis in immunocompromised patients.

Leishmaniasis is a zoonosis caused by a protozoan of the Leishmania genus. First-line treatment for all forms is currently represented by the use of antimony derivatives, although toxic effects and the number of resistant strains in both immunocompromised and immunocompetent patients is increasing. Liposomal amphotericin B (L-AMB) is less toxic, more effective, and better tolerated, especially in human immunodeficiency virus-negative immunocompromised patients. We present 2 cases of transplanted patients affected by visceral leishmaniasis treated successfully with L-AMB.

The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia.

UNLABELLED: We assessed by multiparametric flow cytometry the levels of minimal residual disease (MRD) in 100 adult patients with acute myelogenous leukemia (AML) achieving complete remission after intensive chemotherapy. The aim of the study was to determine the optimal threshold, in terms of residual leukemic cells, and the time point of choice, that is, post-induction (post-Ind) or post-consolidation (post-Cons), able to better predict outcome. By applying the maximally selected log-rank statistics, the threshold discriminating MRD- from MRD+ cases was set at 3.5 x 10(-4) residual leukemic cells, a level that allowed the identification of distinct subgroups of patients, both at post-Ind and post-Cons time points. Post-Cons MRD- patients had a superior outcome in terms of relapse rate, overall survival (OS) and relapse-free survival (RFS) (P<0.001, for all comparisons), regardless of the MRD status after induction. In particular, patients entering MRD negativity only after consolidation showed the same outcome as those achieving early negativity after induction. Multivariate analysis, including karyotype, age, MDR1 phenotype, post-Ind and post-Cons MRD levels, indicated that the post-Cons MRD status independently affected relapse rate, OS and RFS (P<0.001, for all comparisons). IN CONCLUSION: (1) the threshold of 3.5 x 10(-4) is valid in discriminating risk categories in adult AML and (2) post-Cons MRD assessment is critical to predict disease outcome.

Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin's lymphomas.

PURPOSE: This study aimed at correlating Epstein-Barr virus (EBV) infection of systemic AIDS-related non-Hodgkin lymphomas (AIDS-NHL) with the development of a CNS localization of the tumor. PATIENTS AND METHODS: Demographic, epidemiologic, clinical, histologic, and virologic features were collected for all systemic AIDS-NHL patients included in the study (n = 50). Pathologic specimens were classified according to the working formulation for NHL and the Revised European-American Lymphoma classification. EBV infection in tumor tissue samples was studied by EBV small encoded RNA in situ hybridization; EBV-DNA detection in CSF was carried out by nested polymerase chain reaction using Epstein-Barr nuclear antigen-1-specific primers. In addition, selected EBV-positive lymphomas were subjected to a detailed characterization of EBV molecular heterogeneity. RESULTS: Eleven patients had a CNS involvement at some point during their clinical history (four at diagnosis and seven at relapse). Thirty patients (11 with CNS involvement and 19 without) harbored EBV infection of the tumor. Sensitivity, specificity, and positive and negative predictive values of EBV-DNA detection in CSF for CNS involvement by lymphoma were 90%, 100%, 100%, and 97.6%, respectively. Factors significantly predictive of CNS involvement were EBV infection of the tumor (P=.003), an extranodal disease at diagnosis other than CNS (P=.006), and a non-CNS relapse (P=.01). In four cases of CNS involvement, EBV-DNA in CSF preceded any other sign of disease by a mean of 35 days. CONCLUSION: These results show that EBV infection of the tumor clone significantly increases the risk of CNS involvement by systemic AIDS-NHL, without regard of specific molecular features. The detection of EBV-DNA in the CSF of AIDS-NHL patients may select cases with higher risk of CNS involvement and, therefore, may prove useful in the therapeutic stratification of these tumors.

Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation.

A total of 31 adult patients with AML entered in the EORTC/GIMEMA AML-10 trial, who received autologous stem cell transplantation (ASCT) after induction and consolidation chemotherapy, were prospectively evaluated for minimal residual disease (MRD) by multidimensional flow cytometry (MFC). Using a cutoff level of 3.5 x 10(-4) leukemic cells pre-ASCT, 12 patients (39%) were stratified to MRD high-risk group and 19 (61%) into MRD low-risk group. During follow-up, all patients who were in the high-risk group relapsed at a median time of 7 months; in the low-risk group, five patients relapsed at a median time of 11 months and 14 remained in remission for 56 (range 7-80) months (P=0.00004). Longitudinal MFC determinations post-ASCT showed increased MRD levels in three of the five patients who underwent subsequent relapse, while disease recurrence was unpredicted in the remaining two cases. The pre-ASCT MRD status was the factor most strongly associated with relapse risk in the multivariate analysis (P=0.0014). We conclude that: (1) pre-ASCT MRD status predicts successful outcome in patients receiving ASCT; (2) high-dose chemotherapy conditioning regimen followed by ASCT has no impact on the unfavorable prognostic value of high pre-ASCT MRD level; and (3) sequential MRD monitoring post-ASCT may allow the prediction of impending relapse.

Physical methods for preventing deep vein thrombosis in stroke.

BACKGROUND: Deep vein thrombosis (DVT) and resulting pulmonary embolism (PE) are uncommon but important complications of stroke. There is good evidence that anticoagulants can reduce the risk of DVT and PE after stroke, but this benefit is offset by a small but definite risk of serious haemorrhages. Physical methods to prevent DVT and PE (such as compression stockings applied to the legs) are not associated with any bleeding risk and are effective in some categories of medical and surgical patients. We sought to assess their effects in stroke patients. OBJECTIVES: To assess the effectiveness and safety of physical methods of preventing the onset of deep vein thrombosis and fatal or non fatal pulmonary embolism in patients with recent stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched October 2001). In addition we searched the following electronic bibliographic databases: Cochrane Controlled Trials Register (1999, Issue 3), MEDLINE (1966- Jan 2001), EMBASE (1980- Jan 2001) and CINAHL (1982-May 1999). The reference lists of all relevant papers were screened for additional trials. SELECTION CRITERIA: All completed randomised unconfounded trials or controlled clinical trials comparing physical methods in patients allocated to receive physical methods, applied within one week of onset of stroke, with patients allocated to no physical methods. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched for relevant trials and three others independently checked the results. MAIN RESULTS: We identified two small trials which included 123 patients. In one trial of 97 patients, compression stockings were associated with a non significant trend towards a reduction in DVT detected by Doppler ultrasound. In one trial of 26 patients, an intermittent pneumatic compression device was not associated with a significant reduction in DVT detected by 125-I-fibrinogen scanning. Overall, physical methods were not associated with a significant reduction in DVT (Odds ratio 0.59, 95%.CI 0.24-1.48) or death (Odds ratio 5.06, 95% CI 0.96-26.78). REVIEWER'S CONCLUSIONS: There is insufficient evidence from randomised trials to support the routine use of physical methods for preventing DVT in acute stroke.

Physical methods for preventing deep vein thrombosis in stroke.

BACKGROUND: Deep vein thrombosis (DVT) and resulting pulmonary embolism (PE) are uncommon but important complications of stroke. There is good evidence that anticoagulants can reduce the risk of DVT and PE after stroke, but this benefit is offset by a small but definite risk of serious haemorrhages. Physical methods to prevent DVT and PE (such as compression stockings applied to the legs) are not associated with any bleeding risk and are effective in some categories of medical and surgical patients. We sought to assess their effects in stroke patients. OBJECTIVES: To assess the effectiveness and safety of physical methods of preventing the onset of deep vein thrombosis and fatal or non fatal pulmonary embolism in patients with recent stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (last searched June 2003). In addition we searched the following electronic bibliographic databases: Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003), MEDLINE (1966 to June 2003), EMBASE (1980 to June 2003) and CINAHL (1982 to June 2003). The reference lists of all relevant papers were screened for additional trials. SELECTION CRITERIA: Unconfounded randomised controlled trials comparing physical methods for the prevention of DVT with control, in which prophylaxis was started within seven days of the onset of stroke. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched for relevant trials and three others independently checked the results. MAIN RESULTS: We identified two small trials which included 123 patients. In one trial of 97 patients, compression stockings were associated with a non significant trend towards a reduction in DVT detected by Doppler ultrasound. In one trial of 26 patients, an intermittent pneumatic compression device was not associated with a significant reduction in DVT detected by 125-I-fibrinogen scanning. Overall, physical methods were not associated with a significant reduction in DVT during the treatment period in survivors (Odds ratio (OR) 0.54, 95% Confidence Interval (CI) 0.18 to 1.57) or death (OR 1.54, 95% CI 0.5 to 4.77). REVIEWERS' CONCLUSIONS: There is insufficient evidence from randomised trials to support the routine use of physical methods for preventing DVT in acute stroke.

Left atrial and appendage mechanical function after pharmacological or electrical cardioversion in patients with chronic atrial fibrillation: a multicenter, randomized study.

BACKGROUND: Transient atrial and appendage dysfunction occurs after cardioversion of atrial fibrillation. It has been suggested that one component of early dysfunction is related to the method of restoration of sinus rhythm and it is less severe in patients undergoing pharmacological than electrical cardioversion. The aim of this study was to compare left atrial chamber and left atrial appendage mechanical function before and after 48 hours from electrical or pharmacological cardioversion in patients with chronic atrial fibrillation. METHODS: We studied the effects of the mode of cardioversion on Doppler left atrial and appendage function in 19 patients with persistent atrial fibrillation (> or = 4 weeks), who were randomized to pharmacological (quinidine) or electrical cardioversion (protocol: 200, 300, 360 J) after pre-treatment with verapamil. Transthoracic and transesophageal echocardiography were performed before and 48 hours after the restoration of sinus rhythm. To determine left atrial and appendage mechanical dysfunction, the peak A wave velocities were obtained from transmitral flow velocity profiles recorded in the apical 4-chamber view, and peak emptying and filling appendage velocities were measured by the transesophageal approach with the sample volume placed at the orifice of the left atrial appendage. All the patients were pre-treated with verapamil before cardioversion in order to achieve a satisfactory control of heart rate. RESULTS: Mean peak A wave velocities were 0.52 +/- 0.12 m/s in the patients treated electrically and 0.54 +/- 0.08 m/s in those treated pharmacologically (p = NS). Before and after electrical cardioversion, the peak filling velocities of the left atrial appendage were 0.42 +/- 0.17 and 0.43 +/- 0.17 m/s respectively, and the peak emptying velocities 0.30 +/- 0.14 and 0.36 +/- 0.17 m/s respectively; before and after pharmacological treatment, the peak filling velocities were 0.38 +/- 0.1 and 0.43 +/- 0.1 m/s respectively, and the peak emptying velocities were 0.30 +/- 0.13 and 0.43 +/- 0.24 m/s respectively (p = 0.08). CONCLUSIONS: Even a long period of atrial fibrillation does not lead to a marked depression of global left atrial and left atrial appendage function 48 hours after the restoration of sinus rhythm by means of electrical or pharmacological cardioversion. There is no evidence that electrical cardioversion causes greater post-cardioversion atrial and/or appendage dysfunction than pharmacological treatment after 48 hours. Pre-treatment with verapamil may have reduced the dysfunction (probably because of a reduction in mechanical remodeling during atrial fibrillation).

Incidence and predictors of sudden cardiac death during long-term follow-up in patients with dilated cardiomyopathy on optimal medical therapy.

BACKGROUND: In spite of a total mortality reduction in recent years, sudden cardiac death (SD) remains a major problem in patients with idiopathic dilated cardiomyopathy (IDC) and its occurrence is often unpredictable. Furthermore, the risk of SD may change during follow-up because of the natural history of the disease and the effects of therapeutic interventions. In our study, we evaluated the modifications of the risk of SD during follow-up in a cohort of patients with IDC and analyzed the variables predicting SD not only at enrolment but also at the last examination during optimal medical treatment. METHODS: Since 1978, 343 consecutive patients with IDC were enrolled in the Heart Muscle Disease Registry of Trieste (Italy) and submitted to complete invasive and non-invasive study. Patients were re-evaluated usually at intervals of 12 months. RESULTS: After a mean of 68+/-45 months, 125 events (death, heart transplantation or aborted SD) had occurred. The cumulative risk after 5 years was 30%, while after 10 years it almost doubled (54%). During the first 3 months after enrolment, the incidence of SD was high (3%). A plateau, lasting about 3.5 years, followed. A slow but progressive rise in the risk of mortality then occurred (6% at 5 years, 18% at 10 years). No variables evaluated at enrolment were associated with SD at multivariate analysis. On the other hand, the end-diastolic left ventricular diameter (> or = 38 mm/m2) and ejection fraction (< or = 0.30) were predictive of SD if evaluated within 1 year before the event. Beta-blocker treatment was associated with a non-significant reduction of risk. CONCLUSIONS: In patients with IDC the incidence of SD progressively increased during long-term follow-up, especially in those with persistent severe left ventricular dilation and dysfunction who were not on beta-blocker treatment. Serial clinical evaluation may help to select patients at higher risk for SD.

[New operative models for the management of anticoagulant prophylaxis]. / Nuovi modelli operativi per la gestione della profilassi anticoagulante.

Anticoagulant therapy has proven to be effective for patients at risk for thromboembolic disease. Nevertheless, in daily clinical practice the oral anticoagulant therapy (OAT) is underused because it is still considered dangerous and difficult to manage, particularly in patients with chronic non-rheumatic atrial fibrillation. In the most important published studies about this topic we found that only 7-55% of patients with atrial fibrillation were treated with antiplatelet drugs, while 9.9-48.4% took anticoagulant prophylaxis; so, despite a favourable temporal trend after large trials have shown a positive prophylactic effect with antithrombotic drugs, they are underused. It has been estimated that in our country 500,000-600.00 potential patients could have indication for this treatment. Nevertheless, the traditional management of oral anticoagulation is fraught with difficulties such as patients' compliance, reliability of laboratory, global management of the treatment. Undoubtedly, this prophylaxis is very heavy for the patient and the physician often don't like this treatment for its dangerous potential, frequent difficulties of the management, obstacles in the communication among laboratory, physician and patient. Other common problems usually are the distance from patient's home-laboratory, its working hours, means of transportation. It is important a suitable organization and a control of the factors contributing to obtain favourable results for assuring a good cost/benefit ratio of OAT. The relationship among patient-physician-laboratory play a fundamental role. Alternative models are therefore prospected: anticoagulation clinic, computerised decision support software or portable coagulometer. Actually available instruments give us immediately the patients' INR and represent a new option and a promising strategy to monitor these large cohort of patients. Thus the management of OAT can be done by family physicians or by anticoagulant clinic or by patients themselves, after a suitable training period permitting a partial or total self management. These new strategies have improved therapeutic control of oral anticoagulation and in addition to the health advantages both also have economic benefits.

[Impact of chronic atrial fibrillation on cardiovacular mortality]. / Impatto della fibrillazione atriale cronica sulla mortalità cardiovascolare.

The largest cohort studies and a number of other epidemiological or clinical studies have found an increased risk of total, cardiovascular and stroke mortality in patients (both men and women of every age) with chronic non-rheumatic atrial fibrillation (AF) compared to heterogeneous individuals in normal sinus rhythm. These studies suggested that AF increases the probability of death without changing the mode of death. Many excess deaths due to non-rheumatic AF occur soon after the diagnosis of the arrhythmia. Non-rheumatic AF is complicated by the heterogeneity of the underlying heart disease and accompanying medications. Prognosis in non-rheumatic AF is dependent upon the age of the patients and the underlying cardiac conditions but non-rheumatic AF is a potent risk factor for stroke. Stroke in patients with non-rheumatic AF is generally more severe and induces higher mortality. A recent Framingham study has shown that an increased mortality rate persists when adjusted for age, hypertension, smoking, myocardial infarction, congestive heart failure, and stroke or transient ischemic attacks. These results demonstrate that non-rheumatic AF is independently associated with a 50 to 90% increase in the risk of death. Also the excess mortality observed in patients with chronic lone AF supports the independent role of the arrhythmia. The higher incidence of a chronic arrhythmia and the known complications of this condition pose serious problems for health care as our population ages. Passive acceptance of non-rheumatic AF is not correct. In all patients with non-rheumatic AF, restoring and maintaining sinus rhythm for as long as possible needs to be taken into serious consideration. New antiarrhythmic drugs and new strategies for the management of non-rheumatic AF are accumulating. When the arrhythmia is chronic, correct anticoagulant prophylaxis is a must, as several randomized trials have demonstrated a significant reduction in thromboembolic stroke incidence and related mortality with an acceptable hemorrhagic risk by using warfarin.

[Barriers to cardiovascular prevention]. / Gli ostacoli alla prevenzione cardiovascolare.

Data from observational and clinical trials provide a solid basis for the formulation of recommendations for the prevention of coronary artery disease. Numerous obstacles to the implementation of risk reduction interventions have been identified. These include: the patients, physician and health care organization, financial and social barriers, current government social and health policies, and direct and indirect costs. The strategies to overcome these barriers include the development of predictable clinical guidelines for the management of risk factors, the requirement of expertise in risk factor management in training and certification, the implementation of model programs for risk factor management that have been shown to be effective including those utilizing non physician professionals, the inclusion of risk factor management as a key indicator of the level of care in quality assistance programs and the cost-effectiveness of preventive interventions, physician and nursing education programs, referral clinics with subspeciality services, quality programs and standards, legislation and regulation, implementation of patient compliance. In conclusion, the improvement of risk factor management will require an efficient health care system and a coordinated effort by primary care physicians, other professionals (such as cardiovascular physicians and specialized nurses) and government policy.

[Congenital quadricuspid aortic valve]. / Valvola aortica quadricuspide congenita.

A case of a 17-year-old asymptomatic man is reported. The patient had no other cardiac congenital abnormalities. Transthoracic echocardiography revealed a rare quadricuspid aortic valve malformation without aortic regurgitation.

Rituximab for the treatment of patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that originates from antigen-experienced B lymphocytes that do not die and hence accumulate due to external survival signals or undergo apoptosis and are replenished by proliferating precursors. These neoplastic lymphocytes exhibit a characteristic immunophenotype of CD5(+)/CD19(+)/CD20(+)/HLA-DR+/CD23(+)/sIgdim. Thus, the CD20 antigen has been an appealing target for therapy. The introduction of the monoclonal antibody rituximab (anti-CD20) enabled an outstanding advance in CLL treatment. The introduction of this monoclonal antibody into chemotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both untreated and relapsed CLL. Although only preliminary data from phase III confirmatory trials have been reported, the FCR regimen, which combines fludarabine and cyclophosphamide with rituximab, is currently the most effective treatment regimen for CLL patients, and has also been demonstrated to significantly improve overall survival. The success of rituximab and the identification of other CLL lymphocyte surface antigens have spurred the development of a multitude of monoclonal antibodies targeting distinct proteins and epitopes in an attempt to target CLL cells more effectively.

Insights into defibrotide: an updated review.

Defibrotide is a polydisperse oligonucleotide with antiatherosclerotic, anti-inflammatory, anti-ischaemic, pro-fibrinolytic and antithrombotic actions without significant systemic anticoagulant effects. It has been used in the treatment of various cardiovascular disorders, and especially in endothelial complications of allogeneic stem-cell transplantation. We reviewed the published work for the mechanism of action and clinical use of defibrotide to consolidate data and to describe new applications of this drug. We reviewed the most relevant papers on defibrotide published from November 1982 to January 2008. (selected through PubMed), and used recent meeting abstracts as sources for this review. Reports have suggested that defibrotide has clinical efficacy for treatment and prophylaxis of hepatic sinusoidal obstruction syndrome occurring after stem-cell transplantation. Animal models have clearly shown the potential antineoplastic effect of this drug. Further clinical investigations are needed to clarify this new application.

[Anticoagulant prophylaxis: from clinical trials to clinical practice]. / La profilassi anticoagulante: dai grandi trial alla pratica clinica.

Anticoagulant therapy has recently undergone a surge in popularity with the confirmation of its importance in preventing cerebral thromboembolism from atrial fibrillation. Unfortunately oral anticoagulants have an extremely narrow therapeutic index and many physicians are reluctant to treat, particularly old patients, because of the fear of hemorrhagic complications and difficulty of management. The anticoagulant clinic, by improving therapeutic effectiveness and reducing complications, hospitalization and emergency room visits, appears to offer important qualitative and cost advantages over routine medical care. New strategies have been developed for managing care. One promising modality employs patients in their own care by performing their prothrombin time measurement by themselves at home. This model, similar to the way diabetics measure their own blood sugar, is possible as a result of a new class of point-of-care instrumentation for prothrombin testing. These portable monitors can measure a prothrombin time from a finger-stick sample of whole blood and provide a result within seconds. However rigorous studies are necessary to confirm the preliminary results of new management strategies to maximize the benefit-risk ratio of anticoagulant therapy.

[Unusual electrocardiographic changes on exercise testing in patients with angina pectoris]. / Aspetti inusuali dell'elettrocardiogramma da sforzo in pazienti con angina pectoris.

We describe three patients with angina pectoris and uncommon electrocardiographic aspects during exercise test. These cases demonstrate the wide variability of the electrocardiographic changes and symptoms during exercise test and may by considered an example of myocardial response to spasm-related ischemia.

[Lack of tolerance after administration of delayed-action isosorbide-5-mononitrate for 3 days in patients with exercise-induced silent ischemia: control with placebo]. / Assenza di tolleranza dopo somministrazione di isosorbide-5-mononitrato a lento rilascio per tre giorni in pazienti con ischemia silente da sforzo: controllo con il placebo.

In order to assess the development of tolerance we analyzed in a placebo-controlled study the effect of monotherapy with isosorbide-5-mononitrate (IS-5-MN) 60 mg in a controlled release formulation (Durules) once-a-day. The IS-5-MN was evaluated after the first dose and after once-a-day therapy for three days in 11 ambulatory patients (10 males, 1 female, aged 54 +/- 9 years) with stable exercise-induced silent myocardial ischaemia and significant coronary stenoses. The drug was given at 8 o'clock in the morning, and a bicycle ergometer exercise test was performed after 4 hours. The ST segment depression was evaluated by a computer-assisted system. Standing blood pressure decreased during all three periods of active treatment with IS-5-MN, (in comparison with placebo p < 0.001 and p < 0.01, p < 0.01 respectively). Heart rate did not change significantly. Compared with placebo baseline values, ischaemic threshold increased during the first day of treatment (188 sec, p < 0.0001 at 4 hours), and to a lesser extent both in second (103 sec, p < 0.003) and third day (116 sec, p < 0.003). The total exercise time increased during all three days of active therapy but significantly so only during the first day. The exercise stress test performed in the 5th day during placebo demonstrated a high reproducibility of ischaemic-threshold (235 vs 241 sec, p: ns), implying that the improvement during the active treatment with IS-5-MN was not due to a "training effect". Headache in 2 patients was the only significant side-effect.(ABSTRACT TRUNCATED AT 250 WORDS)