Enhancement of noradrenergic neural transmission: an effective therapy of myasthenia gravis: a report on 52 consecutive patients.

Neurochemical, neuroautonomic and neuropharmacological assessments carried out on all our myasthenia gravis (MG) patients showed that they presented a neural sympathetic deficit plus excessive adrenal-sympathetic activity. These abnormalities were registered during the basal (supine-resting) state, as well as after several stress tests (orthostasis, exercise, oral glucose and buspirone). In addition, MG patients showed increased levels of free-serotonin (f5HT) in the plasma, supposedly associated with the increased platelet aggregability which we found in all MG patients. As the above trio of neurochemical disorders (low noradrenergic-activity + high adrenergic-activity + increased f-5HT plasma levels) is known to favor Th-1 immunosuppression + Th-2 predominance, we outlined a neuropharmacological strategy for reverting the above neurochemical disorder. This treatment provoked sudden (acute), and late sustained improvements. Acute effects have been attributed to the increase of alpha-1 activity at the spinal motoneuron level. Late improvements always paralleled a significant normalization of immunological disorders. Complete normalization was registered only in non-thymectomized MG patients.

Effects of buspirone on plasma neurotransmitters in healthy subjects.

Buspirone is an anxiolytic drug which exerts several central effects. It antagonizes presynaptic inhibitory DA2 autoreceptors at dopaminergic neurons and acts as an agonist for 5-HT1A inhibitor autoreceptors at serotonergic cells. Thus, buspirone respectively enhances and depresses the firing rates of both type of neurons. At doses which correlate with dopaminergic stimulation, but not 5-HT inhibition, buspirone also increases the firing rates of the central noradrenergic cells. We measured levels of circulating neurotransmitters before and up to 240 minutes after the oral administration of 20 mg of buspirone in 32 healthy volunteers. Buspirone significantly increased levels of noradrenaline, dopamine, and free serotonin but did not affect levels of adrenaline, tryptophane, or platelet serotonin. Small but significant drops in systolic blood pressure and heart rate were observed after buspirone ingestion. Atropine administration before buspirone ingestion annulled the free serotonin increase as well as systolic blood pressure-heart rate decrease. We found significant positive correlations between noradrenaline and dopamine levels. The strength and significance of these correlations were increased by using the noradrenaline/adrenaline ratio instead of noradrenaline absolute values. This finding indicates that increases in both noradrenaline and dopamine arise from sympathetic nerves rather than the adrenal glands. We also found significant negative correlations between free serotonin increases and systolic blood pressure-heart rate decreases. Our results indicate that buspirone stimulates central sympathetic activity. These acute effects of buspirone are reflected in an increased peripheral neural sympathetic activity, but not adrenal sympathetic activity in healthy individuals. In addition, buspirone increases free serotonin plasma concentrations and decreases systolic blood pressure plus heart rate levels through mechanisms associated with parasympathetic activation.

The serotonin uptake-enhancing drug tianeptine suppresses asthmatic symptoms in children: a double-blind, crossover, placebo-controlled study.

Studies have shown that levels of free serotonin in plasma are increased in symptomatic patients with asthma. In addition, the concentration of free serotonin in symptomatic patients with asthma correlates positively with clinical status and negatively with pulmonary function. Thus, reducing the concentration of free serotonin in plasma might be useful in treating patients with asthma. We studied the effectiveness of tianeptine in treating patients with asthma. Tianeptine is the only drug known to be able to reduce levels of free serotonin in plasma and to enhance uptake by platelets. In this study, 69 children with asthma were assigned in randomized fashion to receive tianeptine and/or placebo in a double-blind crossover trial that lasted 52 weeks. Tianeptine provoked a dramatic and sudden decrease in both clinical rating and free serotonin plasma levels and an increase in pulmonary function.

Neuropharmacologic treatment of bronchial asthma with the antidepressant tianeptine: a double-blind, crossover placebo-controlled study.

Studies have shown the levels of free serotonin in plasma are increased in symptomatic patients with asthma. In addition, the concentration of free serotonin in symptomatic children with asthma correlates positively with clinical status and negatively with pulmonary function (forced expiratory volume in 1 second [FEV1]). Thus, reducing the concentration of free serotonin in plasma may be useful in treating children with asthma. We studied the effectiveness of tianeptine in treating these patients. Tianeptine is the only drug known to be able to reduce the level of free serotonin in plasma and to enhance the uptake by platelets. Sixty-nine of the 82 children with asthma initially enrolled participated in this study. Children were randomized to receive tianeptine or placebo or both in a double-blind crossover trial. The trial lasted 52 weeks. Tianeptine provoked a dramatic and sudden decrease of both clinical rating and free serotonin plasma levels and an increase in pulmonary function.

Coronary flow reserve may predict myocardial recovery after myocardial infarction in patients with TIMI grade 3 flow.

BACKGROUND: The aim of the study was to determine whether the recovery of global and regional left ventricular function after successful percutaneous transluminal angioplasty (PTCA) could be predicted by measuring coronary flow reserve before performing the intervention. METHODS AND RESULTS: Thirty-two patients underwent PTCA 6.9 +/- 3.4 days after a recent myocardial infarction. Coronary flow reserve was determined in the infarct-related artery before PTCA by using an intracoronary Doppler tipped wire. Global and regional wall motion were determined by 2-dimensional echocardiography before the Flowire study and again 7 weeks after the angioplasty. Whereas the global and regional wall motion score indices improved in 20 patients (recovery group), they deteriorated or did not change in 9 patients (nonrecovery group). Coronary flow reserve distal to the lesion in the infarct-related artery was significantly higher in the recovery group (1.43 +/- 0.57 vs 0.98 +/- 0.70, P = .0001). Coronary flow reserve distal to the lesion in the infarct-related artery was < 1.1 in patients whose global or regional left ventricular function did not improve at follow-up, whereas flow reserve ranged between 1.1. and 1.8 while patients in whom left ventricular function improved. CONCLUSIONS: These results suggest that the absence of inducible coronary flow reserve may predict failure of left ventricular systolic function to improve between the first and sixth week after infarction. Measurement of flow reserve with a Flowire at the time of diagnostic angiography after recent myocardial infarction may ultimately prove helpful in deciding whether to proceed with revascularization.

Role of candidate modifier genes on the phenotypic expression of hypertrophy in patients with hypertrophic cardiomyopathy.

BACKGROUND: The phenotypic expression of left ventricular hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) is variable. This phenotypic variability is not completely explained by the responsible mutations or other known factors. Recent data denote a role for the modifier genes and environmental factors. We studied the role of 3 potential modifier genes, i.e., angiotensinogen (AGT), angiotensin II receptor 1a (AT1a), and endothelin-1 (END1) on the phenotypic expression of LVH in patients with hypertrophic cardiomyopathy (HCM). METHODS: The study population was comprised of 108 genetically independent patients with HCM. Left ventricular mass index (LVMI) and LVH score were determined per published protocols. The genotypes of AGT (M235T, T174M, and G-6A), AT1a, and END1 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or mutation-specific PCR (MS-PCR). RESULTS: Male patients had higher mean LVMI and LVH score than female patients (146.0 +/- 33.5 vs 129.4 +/- 33.6, p = 0.01 and 6.0 vs 5.0, p = 0.010, respectively). Gender accounted for 4.8% and 5.4% of the variability of LVMI and LVH score, respectively. The END1 genotypes also had a significant influence on LVH scores accounting for 2.9% of their variability (p = 0.042). The median LVH score was greater in patients with the AA and AG genotypes, as compared to patients with the GG genotype (7.0 vs 5.0, p = 0.034). Neither the AGT nor the AT1 genotypes had a significant influence on the expression of LVH. In multivariate regression analysis, END1 and gender accounted for 7.3% of the variability of the LVH score (p = 0.007). CONCLUSIONS: Our results show that gender and the END1 gene modify the phenotypic expression of hypertrophy in patients with HCM.

Increased levels of free serotonin in plasma of symptomatic asthmatic patients.

BACKGROUND: Previous research has shown that symptomatic asthmatic patients have increased levels of norepinephrine, epinephrine, dopamine, free serotonin, and cortisol in plasma when compared with asymptomatic patients. OBJECTIVE: We investigated the relationship between plasma levels of catecholamines, free serotonin, and cortisol and clinical status and pulmonary function in symptomatic and asymptomatic patients with asthma. METHODS: We compared clinical severity, spirometry, and neuroendocrine factors at weeks 0, 1, 2, 3, and 4 in 57 symptomatic (forced expiratory volume in one second [FEV1] < 70%) and 72 asymptomatic (FEV1 > 80%) asthmatic patients. We used multiple analyses of variance (repeated measures) to interpret the data. In addition, we used the Pearson Product Moment Test to investigate correlations among the different variables. RESULTS: The clinical severity rating and levels of free serotonin, norepinephrine, epinephrine, dopamine, and cortisol were significantly higher in symptomatic asthmatic patients than those in asymptomatic patients (P < .001, in all cases). FEV1 was significantly lower in symptomatic patients than in asymptomatic patients. In symptomatic patients, the level of free serotonin correlated positively with the clinical severity rating (r = .564, P < .01) and negatively with FEV1 (r = -.959, P < .001). In addition, the clinical severity rating showed a negative correlation with FEV1 (r = -.359, P < .01). No significant correlations were found in asymptomatic patients. CONCLUSION: Our finding that free serotonin was the only neuroendocrine factor closely associated with clinical severity and pulmonary function suggests that this factor plays an important role in the pathophysiology of acute asthma.

Plasma neurotransmitters, blood pressure and heart rate during supine resting, orthostasis and moderate exercise in severely ill patients: a model of failing to cope with stress.

BACKGROUND: Previous clinical research has shown that severely ill (somatic) as well as many psychosomatic patients show raised noradrenaline (NA), adrenaline (AD), cortisol, free serotonin (f5HT) and platelet aggregability. Conversely, they show reduced NA/AD plasma ratio and platelet serotonin (p5HT). They also show adrenal hyperresponsiveness to an oral glucose load. These findings are opposed to those observed in depressed patients who show adrenal gland sympathetic hyporesponsiveness and neural sympathetic hyperactivity. OBJECTIVE: To investigate adrenal gland and neural sympathetic systems as well as the other parameters in nondrepressed severely ill patients through the orthostasis exercise stress test which in normals triggers NA but no AD rise. METHODS: We investigated 35 severely ill patients and their age- and sex-paired controls. Systolic, diastolic pulse pressure (PP), heart rate and neuroendocrine parameters were measured supine (0 min), at orthostasis (1 min) and exercise (5 min). A second test was performed 2 weeks later, after atropine injection. Multivariate analysis of variance, paired t test and Pearson product-moment test were employed. RESULTS: The normal PP orthostasis fall was not observed in patients. At this period, an abnormal AD peak substituted the normal NA peak. The normal p5HT-f5HT orthostasis-exercise peaks were absent in patients. Cortisol and platelet aggregability were raised in patients. CONCLUSIONS: Severely ill (somatic) patients responded to the orthostasis-exercise stress test with adrenal and corticosuprarenal but not neural sympathetic activity. They did not show the normal parasympathetic activity at orthostasis. This adrenal gland sympathetic hyperactivity registered in somatic patients is similar to that observed in mammals which fail to cope with stress and contrary to the profile registered in depressed subjects who show NA but not AD rise.

Plasma neurotransmitters and functional illness.

Although the concept of functional illness has blurred boundaries, some consensus exists on its understanding among clinicians. In short, it is easier to conceive than to define functional illness. Semantic and conceptual discussion concerning this issue have been endless. Many links exist that connect brain and body (mind and organs, psyche and soma). Amongst them, neurotransmitters, released by peripheral neurons and some glandular cells (adrenal, enterochromaffin cells, mast cells), are diverted into the bloodstream. Although neurotransmitters cannot cross the blood-brain barrier, basic and clinical research has progressively established the relationship between central and peripheral neurochemical activities. Hence, it is possible to obtain some approach to the central profile through the measurement of circulating neurotransmitters. However, this approach is more reliable if we can measure all circulating factors and, in addition, test the responses to different kinds of challenges (stressors, drugs, etc.). All diseases (somatic, psychiatric and psychosomatic) present some kind of plasma neurotransmitter disturbance; however, only in some has the whole abnormal profile been established. Technical difficulties as well as expensive procedures have interfered with the generalization of this research area. In the present review article, we summarize data quoted from current scientific literature reporting exhaustive research in this area.

Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy.

BACKGROUND: The variability of the phenotypic expression of left ventricular hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) indicates a potential role for additional modifying genes. Variants of angiotensin-I converting enzyme (ACE) gene have been implicated in cardiac hypertrophy. To assess whether ACE genotypes influence the phenotypic expression of hypertrophy, we determined the left ventricular mass index (LVMI) and extent of hypertrophy in 183 patients with HCM. METHODS AND RESULTS: LVMI was derived by the area-length method using two-dimensional echocardiograms. Extent of LVH was determined by a point score method (1 to 10 points). DNA was extracted from blood, and ACE genotyping was performed by polymerase chain reaction (PCR) with an established protocol. Amplification of DNA in the region of polymorphism by PCR of alleles I and D showed 490- and 190-bp products, respectively. ACE genotypes DD, ID, and II were present in 60, 90, and 33 patients with HCM, respectively. In genetically independent patients (n = 108), the mean LVMI (g/m2) was 148 +/- 35.3 in those with DD (n = 35) and 134.2 +/- 33.3 in those with ID and II (n = 73) genotypes (P = .046). LVH score was 6.69 +/- 1.71 in patients with DD and 5.55 +/- 2.19 in those with ID and II genotypes (P = .004). Regression analysis showed that ACE genotypes accounted for 3.7% and 6.5% of the variability of LVMI and LVH score (P = .046 and P = .008, respectively). In 26 patients from a single family, LVMI and LVH score were also greater in patients with DD than in those with ID and II genotypes. ACE genotypes accounted for 14.7% and 10.4% of the variability of the LVMI and extent of hypertrophy, respectively. CONCLUSIONS: ACE genotypes influence the phenotypic expression of hypertrophy in HCM.

Doppler echocardiographic assessment with the continuity equation of St. Jude Medical mechanical prostheses in the mitral valve position.

Evaluation of the St. Jude Medical (SJM) valve in the mitral position with Doppler echocardiography has usually involved the use of gradients across the valve and the application of the pressure half-time (PHT) method to derive a mitral valve area. The purpose of this study was, first, to determine the normal values of effective orifice areas for the SJM valve in the mitral position using the continuity equation, and second, to evaluate whether this parameter provides an improved assessment of valve function. Accordingly, Doppler echocardiography was performed in 40 patients within 6 weeks after valve replacement. All patients were clinically stable, without evidence of valvular dysfunction or aortic insufficiency. Valve size ranged from 23 to 33 mm and ventricular ejection fraction averaged 54 +/- 13%. Effective orifice area was derived by the continuity equation using stroke volume measured in the ventricular outflow tract, divided by the time-velocity integral of the SJM valve jet, and by PHT. Doppler-derived SJM valve mean gradient averaged 4 +/- 2 mm Hg. Effective area by the continuity equation averaged 1.82 +/- 0.36 cm2 (range 1.03 cm2 for a 23 mm valve to 2.63 cm2 for a 31 mm valve) and was smaller than by PHT (mean 3.10 +/- 0.65 cm2, p = 0.0001; range 1.38 to 4.78 cm2). Areas by both methods were smaller than the actual valve orifice area provided by the manufacturer (4.53 +/- 0.80 cm2, p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma neurotransmitters, blood pressure, and heart rate during supine-resting, orthostasis, and moderate exercise conditions in major depressed patients.

Major depressed patients showed greater heart rate, noradrenaline, and free-serotonin values than normal. Conversely, platelet-serotonin values in major depressed patients were significantly lower than normal. Patients registered the normal differential blood pressure reduction during orthostasis. They also revealed progressive and significantly higher heart rate rises during orthostasis and exercise periods, when compared to normals. Whereas noradrenaline showed maximal rises during the two last periods, adrenaline only showed small but significant increase during exercise. The analysis of correlations, together with the above data, suggests that major depressed patients register maximal neural sympathetic activity as well as adrenal glands sympathetic hypoactivity. In addition, these patients show hyperparasympathetic activity, as reflected by the free-serotonin profile. Finally, the fact that both the Hamilton Depression Rating Scale and the self-rating Beck Depression Inventory correlated positively with noradrenaline/adrenaline ratio and free-serotonin values strongly suggests that both neural sympathetic and cholinergic mechanisms are involved in major depression.

Plasma neurotransmitters, blood pressure, and heart rate during supine resting, orthostasis, and moderate exercise in dysthymic depressed patients.

Dysthymic depressed patients showed platelet-serotonin (pS) + plasma-free serotonin values greater than normal as well as plasma noradrenaline values lower than normal during supine resting period (0'). Conversely, no significant differences were observed in the 0' values of any other of the measured parameters: systolic, diastolic and differential blood pressure (SBP, DBP, DP), heart rate (HR), adrenaline (Ad), dopamine (DA), cortisol, and platelet aggregability between patients and controls. Although patients showed then normal DP reduction at orthostasis (1'), this was not prevented by atropine as it does in controls. Patients but not normals showed significant rises of DBP at orthostasis and exercise (5') periods, which were positively correlated with NA rises. On the contrary, the abnormally raised resting fS values registered in patients showed progressive and significant reductions throughout the test that were negatively correlated with DBP-NA values. Adrenaline did not show the normal 5'-fS peak. The above findings suggest that dysthymics show hypoactivity of the two branches of the sympathetic system (neural + adrenal) along with hyperparasympathetic activity. Furthermore, their low NA + high pS values contrast with the high NA + low pS registered in major depressed subjects.

Peripheral blood immunological parameters in long-term benzodiazepine users.

Immunodeficiency is frequently invoked as an ethiopathogenetic factor for many somatic diseases. On the other hand, stress, depression, and psychotic disturbances are associated with severe immunological disorders. Taking into account that the benzodiazepines (BZ) are the psychoactive drugs more widely used than any other to treat psychological disturbances, it seems important to elucidate the immuno-enhancing or immunosuppressant potential of such drugs. Our goal was easily reached, since 69% of the outpatients visiting our Institute are chronic BZ consumers and because neurochemical, hormonal, immunological, and psychiatric investigations are routinely performed on all of our patients. In the present study, immune function was investigated on two occasions: while the patient was on active medication and 15 days after discontinuation. We concluded that chronic consumption of BZ provokes significant immunological disorders that should be further investigated. Said disorders could not be linked to a pre-existing affective disease or psychosis, since we only selected those BZ users in whom psychiatric investigations ruled out a past or present history of major psychiatric disease.

Plasma neurotransmitters and cortisol in chronic illness: role of stress.

We routinely measured plasma neurotransmitters and hormone levels in order to investigate the role of stress on many types of diseases. In this study, we present results obtained from patients with severe chronic diseases. The study sample consisted of 88 patients (asthmatics, ulcerative colitis, Crohn's disease, chronic active hepatitis, chronic relapsing hepatitis, multiple sclerosis, trigeminal neuralgia, systemic lupus erithematous, and rheumatoid arthritis), and their respective controls. Noradrenaline (NA), adrenaline (Ad), dopamine (DA), platelet-serotonin (pS), free-serotonin (fS), growth hormone (GH) and cortisol (CRT) were determined during both exacerbation and improvement periods. A profile compatible with uncoping stress disorder (raised NA-Ad-DA + fS + CRT as well as low pS and NA/Ad ratio) was found during exacerbation periods when compared with improvement, as seen in controls. However, during improvement periods the neurochemical profile remained significantly different from that of normal controls. The neurochemical plus hormonal plasma profiles registered in chronic illness, both during exacerbation and improvement periods, strongly suggest that an uncoping stress mechanism underlies diseases of these patients.

Plasma neurotransmitters throughout an oral glucose tolerance test in non-depressed essential hypertension patients.

The oral glucose tolerance test (OGTT) with plasma neurotransmitter assays and blood pressure measurements were performed on 68 hypertensive (A and B) and 68 paired normal controls (group C). Those patients who failed to show significant or persistent blood pressure reductions throughout OGTT constitute group A (37 subjects); and those who did show significant and persistent reductions constitute group B (31 subjects). The purpose of this study was to assess if there were any significant differences between those patients whose blood pressure levels normalized throughout OGTT and those who didn't and, further, compare them to their controls. In group A, noradrenaline (NA) was high at the 0' (fasting) period, increasing further at 60' and 90'; however, circulating serotonin (p5HT) did not vary throughout OGTT. Group B, although showing high NA at 0', did not show rises afterwards; whereas, significant and sustained p5HT rises registered throughout postprandial periods. In group C, both p5HT and plasma NA showed significant and sustained increases. Therefore, the NA/p5HT ratio is higher in A, than in B and C. Group A patients were awake and alert throughout. Group B patients were mostly drowsy and many slept light and intermittently. Group C subjects slept throughout, dreaming and showing rapid eye movements. Our findings suggest that the hypertensive syndrome is most severe in those patients who do not show a rise in postprandial circulating serotonin (parasympathetic activity), group A, than those who do exhibit such a rise, group B.

Clonidine treatment of acute pancreatitis: report of five cases

Reportamos cinco casos consecutivos de pacientes con pancreatitis aguda, resistente a la terapia convencional, quienes mejoraron dramáticamente con clonidina. Todos los pacientes presentaban niveles plasmáticos muy elevados de noradrenalina, adrenalina y cortisol (indicadores biológicos de estrés, los cuales cayeron bruscamente en cuanto se inició tratamiento con clonidina. Cuando se les practicó el test de clonidina, todos los pacientes tuvieron una hiper-respuesta, lo cual es compatible con situaciones de desadaptación al estrés

Clonidine treatment of acute pancreatitis: report of five cases

Reportamos cinco casos consecutivos de pacientes con pancreatitis aguda, resistente a la terapia convencional, quienes mejoraron dramáticamente con clonidina. Todos los pacientes presentaban niveles plasmáticos muy elevados de noradrenalina, adrenalina y cortisol (indicadores biológicos de estrés, los cuales cayeron bruscamente en cuanto se inició tratamiento con clonidina. Cuando se les practicó el test de clonidina, todos los pacientes tuvieron una hiper-respuesta, lo cual es compatible con situaciones de desadaptación al estrés (AU)

Clonidine treatment of acute pancreatitis: report of five cases.

We report five consecutive cases of patients with acute pancreatitis resistant to conventional treatment who improved dramatically with clonidine. All patients showed greatly elevated noradrenaline, adrenaline and cortisol plasma levels (physiological indicators of stress) which fell abruptly upon initiation of clonidine therapy. The clonidine test performed in the patients showed a hyper-response in all, a reaction consistent with uncoping stress situation. Therefore, we postulate that stress might play a role in the pathogenesis of these patients pancreatic inflammatory disease.

Dramatic improvement with clonidine in acute pancreatitis with elevated catecholamine and cortisol plasma levels: report of five cases.

We report five cases of patients with acute pancreatitis (AP) resistant to conventional treatment who improved dramatically with clonidine. All patients showed greatly elevated plasma levels of noradrenaline (norepinephrine) (NA), adrenalin (epinephrine) (Ad) and cortisol (CRT), physiologic indicators of stress, which decreased abruptly upon initiation of clonidine therapy. The clonidine test performed in the patients showed a hyper-response in all, a reaction consistent with uncoping stress situations. Therefore, we postulate that stress might play a role in the pathogenesis of pancreatic inflammatory disease in these patients.