Intestinal pharmacomanometry and glucose tolerance: evidence for two antagonistic dopaminergic mechanisms in the human.

In this article cumulative data are presented dealing with the existence of more than one dopamine receptor in mammals. In addition, evidence is presented for the existence of two antagonistic dopamine-functional expressions in the human. This fact, along with the disclosure of new dopaminergic agonistic and antagonistic drugs, should prove useful in the management of diseases in which these drugs have proven to be good therapeutic tools.

On the use of clonidine and thioproperazine in a woman with Gilles de la Tourette's disease.

A 25-year-old woman with Gilles de la Tourette's disease was successfully treated with clonidine (an inhibitor of noradrenaline release). However, the drug was stopped because of side effects. Thioproperazine, a phenothiazine derivative which blocks subcortical dopaminergic receptors, suppressed Gilles de la Tourette's symptoms totally. The patient has tolerated the drug well for over a year since its introduction. The pharmacomanometric investigation performed in this patient showed hyperactivity of her noradrenergic system.

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.

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.

Pimozide therapy for trigeminal neuralgia.

Pimozide was compared with carbamazepine in a double-blind crossover trial in 48 patients with trigeminal neuralgia who were refractory to medical therapy. Pimozide treatment produced greater reduction in trigeminal neuralgia symptoms than carbamazepine treatment. All of the pimozide-treated patients improved, while only 56% of carbamazepine-treated patients were relieved of their pain. Although both drugs provoked some adverse effects, it was not necessary to interrupt the trial in any case. After this 24-week trial, all patients began receiving pimozide and were followed up according to an open-label study design. In all cases, the pimozide dosage was progressively reduced until the minimal effective dose was reached. Central and peripheral mechanisms that may underlie pimozide-induced improvement are discussed.

Role of stress in the exacerbation of chronic illness: effects of clonidine administration on blood pressure and plasma norepinephrine, cortisol, growth hormone and prolactin concentrations.

Systolic blood pressure (SBP), diastolic blood pressure (DBP), and plasma norepinephrine (NE), cortisol (CRT), growth hormone (GH) and prolactin (PRL) were studied before and after clonidine (2.5 micrograms/kg i.m.) administration in 193 chronic severely ill patients and 193 normal subjects matched by age and sex. During exacerbation periods (positive manifestations of impairment and progressive disease), the patients showed higher NE, CRT and DBP than the normals or when they were investigated during non-exacerbation periods (92 of the 193). Clonidine induced sharp, marked reductions of NE, CRT and DBP, plus a sudden increase of GH, in all the patients during exacerbation periods. Non-significant reductions of NE, CRT and DBP were observed in normals and in patients during non-exacerbation periods. On the other hand, the GH increase registered during exacerbation periods was of an order of magnitude higher than that registered in normals and in patients during non-exacerbation periods. Significant reduction of SBP was registered both in normals and patients (exacerbation and non-exacerbation periods). Some tendency to PRL lowering was observed during exacerbation periods only. A high positive correlation between NE and DBP (pre- and post-clonidine values) was obtained during exacerbation periods in patients, but not in normals or during non-exacerbation periods in the patients. Similarly, a close negative correlation was obtained between CRT and GH (postclonidine values) during exacerbation periods, but not in normals or during non-exacerbation periods. No significant correlation was found between NE and SBP in any group of subjects. The clonidine-induced changes in GH and CRT observed in the patients during exacerbation periods were in striking contrast to the absence of these changes in depressed patients. This finding is consistent with the low rate of depression (6.7%) registered among our patients during exacerbation periods. The high plasma NE and CRT levels registered in chronic severely ill patients during exacerbation periods reflect a central and peripheral sympathetic hyperactivity, accompanied by an overactivity of the pituitary--adrenocortical axis. The strong reduction of DBP, NE and CRT, along with the sharp and great increase of GH, might be useful as indicators in assessing the exacerbation and progression of severe chronic illnesses.

Psychoneuroendocrinological and immunological parameters in cancer patients: involvement of stress and depression.

Plasma noradrenaline (NA), adrenaline (A), dopamine (DA), platelet serotonin (pS), free serotonin (fS), cortisol (CRT), growth hormone (GH), peripheral blood lymphocytes (lymph), lymphocyte subpopulations (LSS) and CD4/CD8 ratio were serially assessed in 50 non-medicated, advanced cancer patients (spontaneous evolution) and in age- and sex-paired controls. Clonidine tests and psychiatric evaluations were also serially performed. Patients showing long symptomless periods had all normal values except for raised pS, whereas those who remained free of symptoms for only a short time had raised NA, A and CRT, plus lowered pS values. Further increases in NA, A and CRT, plus additional increases in DA and fS, occurred during exacerbation periods, during which times reductions in lymph, LSS and NK also were observed. Patients in terminal stages showed maximal decreases of all neurotransmitters and immunological parameters; only DA and fS remained raised. Psychiatric interviews performed simultaneously with the clonidine tests revealed a low incidence of moderate depression during symptomless periods and no depression during exacerbation periods. Several significant positive and negative correlations between neurotransmitters and immunological parameters were found during exacerbation periods. Pain, although not intense, and other symptoms required occasional administration of low doses of non-opiate analgesics.

Effects of dopaminergic blocking agents on distal colon motility.

Four different dopaminergic blocking agents were able to modify the motility of the distal colon: haloperidol, sulpiride, pimozide, and thioridazine. Haloperidol and sulpiride induced different and frequently antagonistic responses; however, the effects induced by these drugs changed depending on the preexisting pattern of motility. Intestinal tone and sigmoidal or rectal phasic activity predominance are the main factors that influence responses. Biperiden, a centrally acting anticholinergic drug, and dihydroergotamine, an antinoradrenergic drug, annulled the rebound of motility induced by sulpiride in high intestinal-tone and low intestinal-tone subjects, respectively. Our results suggest that the dopaminergic system plays a role in the distal colon motility in humans.

Opposite effects on human distal colon motility of two postulated alpha 2-antagonists (mianserin and chlorprothixene) and one alpha 2-agonist (clonidine).

The effects of two postulated alpha 2-antagonists (mianserin and chlorprothixene) and an accepted alpha 2-agonist (clonidine) on the distal colon motility in five healthy subjects were investigated. Opposite effects were induced by these two kinds of drugs. Distinct and characteristic motility responses were obtained from subjects with low distal colon tone and subjects with high distal colon tone. In addition, different and typical behavior responses paralleled motility changes in the two types of subjects. These results suggest that, at the doses employed in this study, both mianserin and chlorprothixene behave as alpha 2-antagonists when tested on human distal colon motility against a known alpha 2-agonist such as clonidine.

Antidiarrheal effects of dihydroergotamine.

Dihydroergotamine (DHE), an alpha-adrenergic blocking agent, rapidly improved 121 out of 123 diarrheal patients. A hypotonic sigmoid and a hyperreactive rectum were found in these patients. Manometric studies of the distal colon showed that DHE counteracts the rectal hyperactivity and increases sigmoidal tone. On the other hand, anticholinergic drugs and/or emotional stimuli accentuate the rectal hyperactivity of diarrheal patients. Both features could be due to an unbalanced neurologic control of the gastrointestinal tract with dominance of the alpha-adrenergic over the cholinergic activity. Diphenoxylate (DPO) suppressed the diarrhea in two patients not improved by DHE. Furthermore, DPO reinforced the therapeutic success of DHE in 11 lactose intolerance diarrheal patients, suggesting that the two drugs exert their effects by means of different mechanisms.

The "spastic colon" syndrome: therapeutic and pathophysiologic considerations.

Low doses of d-amphetamine plus propranolol rapidly improved the abdominal pain in 165 "spastic colon" patients. Concomitantly, these drugs reduced the sigmoidal hypertonicity and the rectal inhibition found in the manometric studies performed in some of those patients. The sigmoidal tone and phasic activity were also decreased by anticholinergic drugs. These results suggest that a cholinergic-serotonergic hyperactivity of the myenteric plexus may be responsible for the "spastic colon" syndrome.

Distal colon motility in schizophrenic patients.

Although the dopaminergic blocking agents (DBA) haloperidol and sulpiride strongly inhibit distal colon motility in most nonpsychotic subjects (83 per cent), this effect was registered in only 10 per cent of the 30 schizophrenic patients investigated in the present study. In these cases, only sulpiride (an "atypical" DBA) displayed distal colon motility inhibition in schizophrenic subjects. When haloperidol (a "classical" DBA) produced any modification (in 23.3 per cent), this was rather in the nature of an increase in motility. All these cases showed low or absent distal colon motility during preinjection periods. the fact that three different types of antinoradrenergic drugs (dihydroergotamine, phentolamine, and clonidine), but not DBA, inhibited distal colon motility in 90 per cent of the schizophrenic subjects suggests the existence of an overactivity of the noradrenergic system at this peripheral level.

Pharmacomanometric studies of colonic motility as a guide to the chemotherapy of schizophrenia.

Distal colon motility studies performed in 41 psychotic subjects demonstrated that 32 of them had hyperactivity of the noradrenergic system at this peripheral level, while the remaining nine cases showed hyperactivity of the dopaminergic system. The noradrenergic-hyperactive patients fulfilled the Research Diagnostic Criteria of schizophrenia, whereas the dopaminergic-hyperactive patients were diagnosed as having schizoaffective disorders. Noradrenergic-hyperactive subjects were successfully treated with clonidine, a drug which inhibits release of noradrenaline, while dopaminergic-hyperactive subjects were successfully treated with clonazepam, a drug which inhibits release of dopamine. The addition of sulpiride (a postsynaptic dopaminergic blocking agent) and of phentolamine (a postsynaptic noradrenergic blocking agent) to clonidine and clonazepam, respectively, induced further significant improvements in both types of psychotic patients.

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.

Treatment of ulcerative colitis with clonidine.

In the present 30-week, double-blind study of 45 ulcerative colitis (UC) patients treated with prednisone, sulfasalazine, clonidine, or placebo, we found that clonidine (an alpha 2 agonist) and prednisone were effective in treating idiopathic UC. Both drugs were more effective than sulfasalazine. Furthermore, clonidine potentiated prednisone and sulfasalazine effects. Clonidine was chosen because its effect on distal colon motility is similar to thioproperazine, an antipsychotic drug that, despite many adverse effects, possesses powerful anti-UC properties. Rating scales were outlined in order to evaluate clinical, endoscopic, histologic, and radiologic changes. Plasma cortisol levels, sedimentation rate, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, and other biochemical parameters were determined to assess the efficacy of each drug. Distal colon motility changes were also assessed. All our UC patients showed raised cortisol plasma levels and low sigmoidal tone during relapse periods. These parameters were reversed during remission periods. Peripheral and central mechanisms are discussed.

Stress versus depression.

1. Exhaustive evidence is quoted showing that uncontrollable (uncoping) stress provoked in experimental mammals leads to depletion of central noradrenergic activity+ adrenomedullary-cortical gland hyperactivity. These physiological disorders cause the typical neuroendocrine peripheral profile: a) raised catecholamines (CA) in plasma [noradrenaline (NA)+adrenaline (Ad)+dopamine (DA), b) reduced NA/Ad ratio in plasma and c) raised plasma cortisol. 2. Exhaustive evidence is quoted which indicates that severely ill humans show peripheral neuroendocrine profile similar to that found in mammals submitted to uncontrollable stress situation. Further, the NA/Ad ratio does not increase but decreases during orthostasis and exercise stress challenges, as well as oral glucose stress (tolerance) test. 3. Exhaustive evidence is quoted which indicates that endogenous depressed subjects show a neuroendocrine profile opposite to that observed in stressed mammals and severely ill humans. This profile consists of central NA (neural sympathetic) hyperactivity+ adrenomedullary glands hyporresponsivity. These disorders are reflected in a three to ten fold increase of the NA/Ad ratio in plasma. 4. Exhaustive evidence is also quoted showing that dysthymic depressed patients show low plasma catecholamines+low NA/Ad plasma ratio (< 2) during supine-resting condition, it is normalized at orthostasis and exercise periods. 5. It is quoted evidence showing that whereas platelet serotonin is increased in dysthymics, the same is reduced in both endogenous depressed and stressed mammals as well as severely ill humans. 6. It is quoted evidence showing that free serotonin in plasma is greatly raised in uncoping stressed mammals and severely ill humans. The same parameter is normal or slightly increased in dysthymic and endogenous depressed humans. These findings are consistent with the increased platelet aggregability observed in "uncontrollable" stressed mammals and in severely ill, but not depressed patients. 7. It is also quoted evidence showing that whereas parasympathetic activity is absent in uncontrollable stressed mammals and severely ill humans, the same is increased in both types of depressed humans. 8. According to the above, the authors postulate the existence of 3 distinct central+ peripheral neuroendocrine profiles for endogenous depression, dysthymic depression and maladaptation to stress syndrome. These different profiles should lead researchers to attempt different therapeutical approach. 9. In view of the fact that the authors found much clinical overlap among the three syndromes (endogenous depression, dysthymic depression and severely ill patients), they believe that a differential diagnosis should be based on neurochemical, neuroendocrine, physiologic, metabolic and neuropharmacological grounds. 10. The experimentally induced uncontrollable stress (behavioral despair) syndrome in mammals should not be used as a valid model of human depressive syndrome.

Distal colon motility and clinical parameters in depression.

Eighty-six patients suffering from nonpsychotic unipolar major depressive disorder, according to Research Diagnostic Criteria, were rated on a modified Hamilton Rating Scale for Depression (HRS). All completed the self-rating Beck Depression Inventory (BDI). Distal colon motility (dcm) studies, performed in all the patients, differentiated two types: low intestinal tone (low-IT) = 40 subjects, and high intestinal tone (high-IT) = 46 subjects. Low-IT depressed patients showed a statistically significant preponderance in the HRS items 'retardation', 'somatization', 'fatigability', 'hypochondriasis' and 'obsessional symptoms'. The high-IT depressed patients, on the other hand, showed preponderance in the items 'guilt', 'suicide', 'insomnia', 'agitation', 'anxiety psychic', 'loss of insight', 'depersonalization' and 'paranoid symptoms'. A positive correlation (r) was found between HRS- and BDI-mean total scores. In addition, a positive correlation (r) was found between HRS scores and distal colon tone in high-IT patients, although the same was not true for low-IT patients. Our results suggest the existence of two subtypes of depressive syndromes, distinguishable on the basis of distal colon motility profiles.

Distal colon motility as a predictor of antidepressant response to fenfluramine, imipramine and clomipramine.

The present study gathers results obtained in the treatment of 86 depressed outpatients. The patients were grouped according to their distal colon tone, low-IT and high-IT. All the patients fulfilled the Research Diagnostic Criteria for nonpsychotic unipolar major depressive disorder and were rated on a slightly modified 18-item Hamilton Rating Scale for Depression (HRS). They also completed the 21-item self-rating Beck Depression Inventory (BDI). The 46 subjects from the high-IT group and the 40 subjects from the low-IT group were divided into three subgroups each for double-blind trials performed with clomipramine (CMI), imipramine (IMI), and fenfluramine (FENF). Normalization of HRS and BDI scores and reduction of IT were obtained with IMI and FENF but not CMI in high-IT patients; whereas normalization of both scores and increase in IT were obtained with CMI but not with IMI or FENF in low-IT patients. FENF was not tolerated in this last group. HRS and BDI scores correlated well during in-treatment periods. Our results suggest that distal colon tone is a guide to determining the pharmacotherapy in the depressive disorders. Furthermore, it was shown that FENF is a useful anti-depressant drug in one type of patient.

Differential effect of footshock stress on humoral and cellular immune responses of the rat.

Recent, mostly "in vitro", studies indicate that certain stress protocols may affect differentially immune mechanisms. In agreement with these studies, our "in vivo" results show that 4 consecutive days of intermittent footshock, in rats, depressed the primary antibody response, to a thymic dependent antigen, but enhanced the graft-versus-host response and the capacity to reject an inocula of Walker carcinoma cells. Thus it is concluded that footshock stress is capable of oppositely affecting "in vivo" produced humoral and cellular immune responses.