[Show abstract][Hide abstract] ABSTRACT: We have demonstrated that anorexia nervosa is underpinned by overwhelming adrenal sympathetic activity which abolishes the neural sympathetic branch of the peripheral autonomic nervous system. This physiological disorder is responsible for gastrointestinal hypomotility, hyperglycemia, raised systolic blood pressure, raised heart rate, and other neuroendocrine disorders. Therefore, we prescribed neuropharmacological therapy to reverse this central and autonomic nervous system disorder, in order to normalize the clinical and neuroendocrine profile.
The study included 22 female patients with anorexia nervosa (10 restricted type, 12 binge-eating type) who received three months of treatment with amantadine 100 mg/day. We measured blood pressure, heart rate, and circulating neurotransmitters, (noradrenaline, adrenaline, dopamine, platelet serotonin, free plasma serotonin) during supine resting, one minute of orthostasis, and a five-minute exercise test before and after one, two, and three months of treatment with amantadine, a drug which abrogates adrenal sympathetic activity by acting at the C1(Ad) medullary nuclei responsible for this branch of the peripheral sympathetic activity.
We found the amantadine abolished symptoms of anorexia nervosa from the first oral dose onwards. Normalization of autonomic and cardiovascular parameters was demonstrated within the early days of therapy. Abrupt and sustained increases in the plasma noradrenaline:adrenaline ratio and disappearance of abnormal plasma glucose elevation were registered throughout the three-month duration of the trial. Significant and sustained increases in body weight were documented in all cases. No relapses were observed.
We have confirmed our previously published findings showing that the anorexia nervosa syndrome depends on the hypomotility of the gastrointestinal tract plus hyperglycemia, both of which are triggered by adrenal sympathetic hyperactivity. The above neuroendocrine plus neuroautonomic and clinical disorders which underpinned anorexia nervosa were abruptly suppressed since the first oral dose of amantadine, a drug able to revert the C1(Ad) over A5(NA) pontomedullary predominance responsible for adrenal and neural sympathetic activity, respectively.
[Show abstract][Hide abstract] ABSTRACT: Plasma glucose level depends on the peripheral intra-islet crosstalk between A cells (glucagon) + B-cells (insulin) and D-cells (somatostatin). Gastrointestinal hormones (secretin, CCK-PZ, gastrin, and serotonin) modulate the glucose- and amino acids-induced secretions of insulin and glucagon, respectively. Serotonin (5-HT) arose from the enterochromaffin cells during postprandial periods excites basal but inhibits excited B-cells. Serotonin excites adrenal glands that release adrenaline (Ad) + dopamine (DA). The former is positively correlated with hyperglycemia, whereas DA antagonizes this effect. Noradrenaline (NA) released from both sympathetic nerves and adrenal glands modulates the Ad release from this latter and excites A-cells. Thus, NA attenuates the hyperglycemic effects triggered by Ad. Dopamine released from both sources, adrenal glands and peripheral sympathetic nerves, antagonizes Ad-induced hyperglycemia plus the NA-triggered glucagon secretion. Both plasma insulin and glucagon cross the blood-brain barrier and excite A5(NA) and C1(Ad) neurons, respectively. C1 (Ad) neurons send excitatory drives to both islet A-cells and adrenal glands. Both central nervous system A5(NA) and C1(Ad) nuclei interchange inhibitory axons. Predominance of the former redounds in hyperinsulinism plus hypoglycemia, whereas the latter axis is responsible for hyperglucagonemia + hyperglycemia. In addition, the dorsal raphe serotonergic and the median raphe serotonergic nuclei interchange excitatory axons with the C1 (Ad) and the A5(NA) neurons, respectively. Hence, the former binomial axis (responsible for uncoping stress) is positively correlated with the hyperglycemic syndrome, whereas the A5(NA) + median raphe serotonergic binomial is correlated with hypoglycemia. Hence, the insulin resistance disorder should be underlain by the overactivity of both axes simultaneously. The above pathophysiological mechanisms are consistent with the successful neuropharmacological manipulations addressed to treat these neuroendocrine syndromes. Finally, one of the showiest findings derived from our research work arises from the unbalance between the DA versus 5-HT circulating parameters demonstrating that absolute predominance of the former is always paralleled by hypoglycemia (endogenous depression syndrome), whereas the opposite profile is registered in mammals affected by hyperglycemia (dysthymic depression and uncoping stress syndromes).
American journal of therapeutics 11/2010; 20(4):349-62. DOI:10.1097/MJT.0b013e318235f295 · 1.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of our study was to determine the central and peripheral autonomic nervous system profiles underlying anorexia nervosa (AN) syndrome, given that affected patients present with the opposite clinical profile to that seen in the hyperinsulinism syndrome.
We measured blood pressure and heart rate, as well as circulating neurotransmitters (noradrenaline, adrenaline, dopamine, plasma serotonin, and platelet serotonin), using high-performance liquid chromatography with electrochemical detection, during supine resting, one minute of orthostasis, and after five minutes of exercise. In total, 22 AN patients (12 binge-eating/purging type and 10 restricting type) and age-, gender-, and race-matched controls (70 ± 10.1% versus 98 ± 3.0% of ideal body weight) were recruited.
We found that patients with AN had adrenal sympathetic overactivity and neural sympathetic underactivity, demonstrated by a predominance of circulating adrenaline over noradrenaline levels, not only during the supine resting state (52 ± 2 versus 29 ± 1 pg/mL) but also during orthostasis (67 ± 3 versus 32 ± 2 pg/mL, P < 0.05) and after exercise challenge (84 ± 4 versus 30 ± 3 pg/mL, P < 0.01).
Considering that this peripheral autonomic nervous system disorder depends on the absolute predominance of adrenomedullary C1 adrenergic nuclei over A5 noradrenergic pontine nucleus, let us ratify the abovementioned findings. The AN syndrome depends on the predominance of overwhelming adrenal sympathetic activity over neural sympathetic activity. This combined central and autonomic nervous system profile contrasts with that registered in patients affected by hyperinsulinism, hypoglycemia, and bulimia syndrome which depends on the absolute predominance of neural sympathetic activity.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 09/2010; 3:311-7. DOI:10.2147/DMSOTT.S10744
[Show abstract][Hide abstract] ABSTRACT: Considering that glutamatergic axons innervate the C1(Ad) medullary nuclei, which are responsible for the excitation of the peripheral adrenal glands, we decided to investigate catecholamines (noradrenaline, adrenaline and dopamine) plus indolamines (plasma serotonin and platelet serotonin) at the blood level, before and after a small oral dose of amantadine, a selective NMDA antagonist. We found that the drug provoked a selective enhancement of noradrenaline plus a minimization of adrenaline, dopamine, plasma serotonin and platelet serotonin circulating levels. Significant enhancement of diastolic blood pressure plus reduction of systolic blood pressure and heart rate paralleled the circulating parameter changes. The above findings allow us to postulate that the drug was able to enhance the peripheral neural sympathetic activity. Minimization of both adrenal sympathetic and parasympathetic activities was also registered after the amantadine challenge. The above findings supported the postulation that this drug should be a powerful therapeutic tool for treating diseases affected by adrenal sympathetic hyperactivity.
[Show abstract][Hide abstract] ABSTRACT: Objective: Investigation of the effects of an oral administration of a small dose of l-glutamic acid on the two peripheral sympathetic branches (neural and adrenal) of the autonomic nervous system. Research design and methods: Circulating neurotransmitters and cardiovascular parameters were assessed in 28 healthy volunteers before and after the administration of 500 mg of l-glutamic acid or placebo. Results: The drug triggered a significant and sustained enhancement of the noradrenaline and dopamine circulating levels which were paralleled and positively correlated with the diastolic blood pressure increases. Conversely, both platelet and plasma serotonin showed significant falls throughout the test. Significant positive correlations were registered between noradrenaline, dopamine, and noradrenaline/dopamine ratio versus diastolic blood pressure but not versus systolic blood pressure or heart rate. Conclusion: The above results allowed us to postulate that the drug provoked a significant enhancement of peripheral neural sympathetic activity and the reduction of adrenal sympathetic and parasympathetic drives. Both sympathetic branches are positively correlated with the A 5 noradrenergic and the C 1 adrenergic pontomedullary nuclei, which interchange inhibitory axons that act at post-synaptic α 2 inhibitory autoreceptors. In addition, we discussed the mechanisms able to explain why the drug acted preferentially at the A 5 noradrenergic rather than the C 1 adrenergic nuclei.
[Show abstract][Hide abstract] ABSTRACT: The purpose of the trial was to examine the effects of amantadine, a N-methyl-D-aspartate (NMDA) antagonist, on the oral glucose tolerance test (OGTT) plus insulin, glucagon and neurotransmitters circulating levels. Previous findings showed that hyperinsulinism and type 2 diabetes are positively associated with neural sympathetic and adrenal sympathetic activities, respectively. These peripheral sympathetic branches depend on the pontine (A(5)-noradrenergic) and the rostral ventrolateral (C(1)-adrenergic) medullary nuclei. They are excited by glutamate axons which act at NMDA postsynaptic receptors.
One OGTT plus placebo and one OGTT plus oral amantadine test were carried out two weeks apart in 15 caucasic normal voluntary humans. Noradrenaline, adrenaline, dopamine, plasma-free serotonin, platelet serotonin, glucose, glucagon, and insulin were measured throughout the 180-minute testing period.
Maximal reductions of plasma glucose and glucagon plus exacerbated insulin rises were significantly greater throughout the oral glucose plus amantadine test than those registered throughout the oral glucose plus placebo challenge. The above findings were paralleled by greater than normal noradrenaline/adrenaline plasma ratio increases. In addition, maximal reductions of the platelet serotonin and plasma serotonin circulating values contrasted with the normal rises of these parameters, always registered during the glucose load plus placebo challenge.
This study supports the theory that amantadine might be a powerful antidiabetic tool and could be added to the therapeutic arsenal against type 2 diabetes.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 12/2009; 2:203-13.
[Show abstract][Hide abstract] ABSTRACT: El insomnio es un problema de salud importante y prevalente entre personas adultas. Para abordar este problema, se compararon veinticuatro adultos insomnes y no insomnes mediante un diseño causal-comparativo, ex post facto, con base en medidas psicológicas y polisomnográficas. Se determinaron en ambos grupos algunos parámetros psicológicos e indicadores polisomnográficos. En las seis medidas psicológicas revisadas se encontraron diferencias significativas entre ambos grupos en cinco medidas. En las restantes medidas polisomnográficas también se encontraron diferencias significativas en la totalidad. Una de las aportaciones de este estudio fue la identificación de instrumentos psicológicos para mejorar la relación costo-eficiencia de este tipo de investigaciones. Se ofrecen recomendaciones para el entrenamiento y tratamiento y se sugieren algunas investigaciones a realizarse en esta área. En estudios futuros se propone combinar las mediciones polisomnográficas con las mediciones neuroendocrinas y psicológicas para mejorar los perfiles diagnósticos.
[Show abstract][Hide abstract] ABSTRACT: Drugs that inhibit the uptake of serotonin at the synaptic level, such as doxepin, are able to counteract hyperinsulism-induced hypoglycemia. Thus, we postulated that
tianeptine, a drug which facilitates the uptake of serotonin at both synaptic and platelet levels, might display an antidia¬betogenic effect. We investigated the oral glucose tolerance test (OGTT) + placebo in 38 normal humans. A second OGTT + tianeptine was performed 2 weeks later in the same subjects. We found that tianep¬tine potentiated a significant and sustained increase of insulin registered during the OGTT, further evidenced by a decrease in plasma glucose. Significant increases of the plasma noradrenaline (NA)/adrenaline (Ad) ratio paralleled insulin rises. Additionally,
the positive correlation observed between the NA/Ad plasma and insulin levels is con¬sistent with the well-known fact that insulin crosses the blood-brain barrier and excites the central nervous system (CNS)-norad¬renergic neurons responsible for peripheral sympathetic nerve activity. Furthermore, significant reductions of both circulating serotonin (plasma serotonin plus platelet se¬rotonin) registered throughout the tianeptine + glucose challenge. This observation sup¬ports the postulation that the drug interferes with the normal peripheral parasympathetic activity demonstrated throughout the OGTT. This hypoparasympathetic effect triggered by the drug is responsible for the hyposecre¬tion of serotonin from the enterochromaffin cells. In conclusion, tianeptine potentiates the insulinogenic effect of OGTT throughout both CNS and peripheral mechanisms. Both effects depend on the drug's interference at CNS plus peripheral levels.
The journal of applied research 01/2009; 9(3):76-87.
[Show abstract][Hide abstract] ABSTRACT: The circulating neurotransmitters nora¬drenaline, adrenaline, dopamine, platelet serotonin, plasma serotonin, and trypto¬phan were assessed before and after a desipramine challenge (10 mg injected intramuscularly) in patients affected by neural sympathetic predominance (N), adrenal sympathetic predominance (A), and normal controls (C). Maximal increases of the noradrena¬line/adrenaline ratio were found in type N patients, whereas minimal but signifi¬cant increases were registered in type A patients. In addition, statistical data showed that dopamine arose from sym¬pathetic nerves in type N subjects and from the adrenal glands in type A patients. Successful neuropharmacological therapy guided by the above neuro¬transmitter profiles were able to normal¬ize both the clinical syndromes plus the autonomic nervous system disorders. With respect to this, we present the results obtained in 154 type N and 110 type A patients treated and carefully controlled throughout long time periods. According to all the above, we postulate the existence of 2 types of autonomic disorders that underlie diseases and, in addition, we found that type N and type A diseases are frequently associated with the TH-1 and TH-2 immunological profiles, respectively.
The journal of applied research 01/2008; 2(2):151-167.
[Show abstract][Hide abstract] ABSTRACT: We investigated the changes of circulating neurotransmitters during the wake-sleep cycle in order to find possible correlations with the activity of central neurocircuitry functioning. Noradrenaline (NA), adrenaline (Ad), dopamine (DA), platelet serotonin (p-5HT), plasma serotonin (f-5HT) and plasma tryptophan (TRP) were assessed during the morning (supine resting + 1-min orthostasis + 5-min exercise) and at night (supine resting + slow wave sleep (SWS) + REM sleep). Only NA increased in the plasma during short-lasting (1-min) orthostasis morning waking period. Both NA and Ad rose during moderate exercise. The nocturnal results demonstrated that whereas Ad dropped during the supine resting, NA did not fall until SWS period. Although DA did not show significant changes during the nocturnal test, the NA/DA ratio showed significant reduction. The analysis of correlations supports the postulation that this finding reflects the DA modulatory role on neural sympathetic activity. Both f-5HT and p-5HT values were lower during sleep cycle than wake periods. However, they showed progressive rises during sleep stages. Conversely, the f-5HT/p-5HT ratio showed significantly greater values during the SWS period than during supine resting and REM periods. These findings are consistent with the postulation that f-5HT/p-5HT ratio is positively associated with parasympathetic activity during the sleep-cycle. We concluded that the profile of sleep-cycle circulating neurotransmitters differs from that obtained during waking periods. According to the above, we attempted to correlate the profile of circulating neurotransmitters with the very well-known central neurocircuitry functioning during wake-sleep cycle, in experimental mammals.
[Show abstract][Hide abstract] ABSTRACT: 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.