5-HIAA Excretion Research Articles

Cardiac disease and midgut carcinoid syndrome

Abstract Background Valvular heart disease is a well known complication of the midgut carcinoid syndrome but its impact on survival and effects of modern tumour treatment remain to be analysed. Methods In a prospective study cardiac abnormalities and clinical outcome were analysed in 64 consecutive patients with high urinary excretion of the serotonin metabolite 5-HIAA and carcinoid tumours with liver metastases (mean(s.d.) follow-up 119(7) months). A tumour reduction programme by radical surgery alone (including hemihepatectomy) or with hepatic artery embolization following primary surgery (in bilobar liver disease) was offered to all patients. At entry into the study, patients underwent Doppler echocardiography, exercise electrocardiography, Holter monitoring and urinary 5-HIAA determination. Results At follow-up, patients were grouped according to clinical outcome. Twenty-four patients were alive, 11 after radical surgery alone (group 1) and 13 after embolization plus octreotide (group 2). Forty patients had died during follow-up (group 3), three with radical surgery (unrelated disease) and 27 patients with embolization plus octreotide. Ten deceased patients had medical therapy alone after primary surgery owing to complicating diseases. The mean 5-HIAA levels before treatment were lower in group 1 (185 mol per 24 h) than in group 2 (956 (mol per 24 h) or group 3 (566 (mol per 24 h). Tricuspid valve structural abnormalities (TSA) were found in 13, 38 and 33 per cent, and holosystolic tricuspid regurgitation (TR) in 36, 54 and 60 per cent of patients in groups 1, 2 and 3 respectively. No patient had pulmonary stenosis, but 9 per cent (group 1), 15 per cent (group 2) and 13 per cent (group 3) had holodiastolic pulmonary regurgitation. A novel index (TSA–TR) of TSA (0–4) and TR (0–4) was formed. Patients with TSA–TR (3 had significantly (P = 0·025) higher 5-HIAA levels than patients with an index (1. Patients with 5-HIAA levels above 500 (mol per 24 h demonstrated a significantly (P = 0·04) higher late-to-early peak ratio (A/E) of diastolic tricuspid Doppler flow than patients with 5-HIAA levels less than 500 (mol per 24 h. Of the six patients who suffered cardiac death, five died from ischaemic heart disease or sudden death and one from advanced right heart failure. Conclusion Tricuspid abnormalities were common findings in patients with the midgut carcinoid syndrome and severe findings were related to high urinary excretion of 5-HIAA. The highest initial hormone levels were seen in one of the surviving groups. Sudden or ischaemic heart death was more common than death from right-sided heart failure.

Peripheral markers of serotonergic and noradrenergic function in post-pubertal, caucasian males with autistic disorder.

Some studies have suggested that disorders in the peripheral and central metabolism of serotonin (5-HT) and noradrenaline may play a role in the pathophysiology of autistic disorder. This study examines serotonergic and noradrenergic markers in a study group of 13 male, post-pubertal, caucasian autistic patients (age 12-18 y; I.Q. > 55) and 13 matched volunteers. [3H]-paroxetine binding Kd values were significantly higher in patients with autism than in healthy volunteers. Plasma concentrations of tryptophan, the precursor of 5-HT, were significantly lower in autistic patients than in healthy volunteers. There were no significant differences between autistic and normal children in the serum concentrations of 5-HT, or the 24-hr urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA), adrenaline, noradrenaline, and dopamine. There were no significant differences in [3H]-rauwolscine binding Bmax or Kd values, or in the serum concentrations of tyrosine, the precursor of noradrenaline, between both study groups. There were highly significant positive correlations between age and 24-hr urinary excretion of 5-HIAA and serum tryptophan. The results suggest that: 1) serotonergic disturbances, such as defects in the 5-HT transporter system and lowered plasma tryptophan, may play a role in the pathophysiology of autism; 2) autism is not associated with alterations in the noradrenergic system; and 3) the metabolism of serotonin in humans undergoes significant changes between the ages of 12 and 18 years.

Circadian periodicity of urinary volume, creatinine and 5-hydroxyindole acetic acid excretion in healthy Indians

The circadian periodicity of urinary output, creatinine (Cr) and 5-hydroxyindole acetic acid (5-HIAA) excretion was studied under near-tropical conditions in 130 healthy volunteers (65 men and 65 women, 16–75 years of age) with a diurnal activity from about 06:30 to about 22:00 and nocturnal rest. These volunteers were divided into 4 groups, 16–30, 31–45,46–60 and 61–75 years of age, comprising 20, 20,15 and 10 participants of each gender, respectively. A marked circadian rhythm was recorded for urine volume, Cr and 5-HIAA excretion in healthy Indians of different ages. The acrophase tended to be delayed in the older age group. The relative amplitude decreased with advancing age, notably in women. Overall, men produced a larger urine volume as compared to women. Excretions of Cr and 5-HIAA in healthy Indian volunteers of different ages may be influenced by diet, societal relations, climate and/or geographic location. The contribution of such factors in metabolism and degradation warrants further study.

GYNECOLOGIC LAPAROSCOPIC SURGERY IS NOT ASSOCIATED WITH AN INCREASE OF SEROTONIN SECRETION

S253 Gynecologic laparoscopic (GL) surgery is associated with a high incidence of postoperative nausea and vomiting (PONV). Numerous studies have shown the beneficial effects of 5-HT3 antagonists in this setting 1, but the mechanism of action of the specific 5-HT3 antagonists after GL procedures is still not elucidated. After institutional ethics committee and written informed consent was obtained, 40 patients scheduled for elective laparoscopic (group A) or laparotomy (OL) (group B) were prospectively included in the study. Premedication, anesthetic techniques and postoperative pain treatment were standardized. The excretion of urinary 5-hydroxyindoacetic acid (5-HIAA) corrected to creatinine was measured in all patients immediately after induction of anesthesia and regularly repeated until the 9th hour following induction. The two groups were comparable with regard to demographic, although the ages were higher and the duration of surgery longer in group B (p<0.05). Postoperative morphine requirements were higher in group B (p<0.05). The excretion of 5-HIAA/creatinine was similar in both groups. The incidence of nausea was 50% and vomiting 35% in group A versus 60% for nausea and 15% for vomiting in group B (NS). The creation of a pneumoperitoneum during GL surgery is not associated with an increase of 5-HIAA excretion. We conclude that PONV after GL procedure is not explained by an increase of serotonin secretion. (Figure 1)Figure 1: Urinary excretion of 5-HIAA/creatinine in group A (GL) and B (OL) from t0 (= induction of anesthesia) to t9 (= 9 hours after induction). Results are expressed as mean +/- SD.

Urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion before and during cisplatin chemotherapy in patients with intrathoracic malignancy

Background : Nausea and vomiting associated with chemotherapy are common side effects which remain difficult to control. Acute phase nausea and vomiting (0-24 hours after induction of chemotherapy) parallels plasma serotonin release, which explains the effectiveness of receptor antagonists. Serotonin released from gastrointestinal enterochromaffin cells may mediate chemotherapy-induced emesis. In this study, we analyzed urinary excretion of 5-HIAA, the main metabolite of serotonin. Methods : Eight men and four women were studied in their cisplatin chemotherapy cycle. Urinary 5-hydroxyindoleaoetic aicd (HIAA) levels were determined before and during a 24-hour period under ondansetron prophylaxis. Results : Urinary 5-HIAA excretion for a 24-hour period was increased in all patients after induction of cisplatin (P=0.002). Conclusion : Cisplatin chemotherapy is associated with serotonin release in the acute phase. Our finding may provide evidence for a relationship between emesis and serotonin following cisplatin chemotherapy.

Urinary 5-Hydroxyindoleacetic acid (5-HIAA) excretion during multiple-day high-dose chemotherapy

Highly emetogenic drugs such as cisplatin induce an increase in the urinary 5-hydroxyindoleacetic acid (5-HIAA) level, the main metabolite of serotonin (5-HT), within the first 24h following a single infusion, thus providing a possible cause for acute emesis and an explanation for the action of 5-HT3 antagonists. No further excretion peaks have been observed, suggesting that additional or serotonin-independent mechanisms cause delayed emesis. Our aim was to study the mechanisms behind emesis seen during a highly emetogenic chemotherapy regimen given as a continuous infusion over several days. Seven women treated with a 4-day high-dose chemotherapy (HDCT) regimen for breast cancer entered the study. Pooled urine samples were collected prior to and during chemotherapy for determining 5-HIAA excretion. An excretion peak in the urinary 5-HIAA level was observed within the first 24h with no further peaks thereafter. Thus, the mechanisms behind the emesis experienced during this highly emetogenic multiple-day chemotherapy regimen from days 2–3 onwards would appear to be at least partially serotonin independent and would not be expected to be completely relieved by 5-HT3 antagonists alone.

Reduced Urinary Excretion of Dopamine and Metabolites in Chronic Renal Parenchymal Disease

Background: Chronic renal parenchymal diseases are accompanied by a progressive loss of tubular units endowed with the ability to synthesise dopamine from L-3,4-dihydroxyphenylalanine (L-DOPA), and preliminary evidence has suggested that the urinary excretion of free dopamine may be reduced in these disorders. However, it is well recognised now that under in vitro conditions, dopamine newly synthesised in tubular epithelial cells undergoes extensive deamination to 3,4-dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase (MAO); a small amount of the amine is converted to homovanillic acid by both MAO and catechol-O-methyltransferase (COMT) and a minor amount is methylated to 3-methoxytyramine. Aims: The present study aimed at examining the relationship between renal function and daily urinary levels of L-DOPA, free dopamine and its main metabolites, DOPAC and homovanillic acid (HVA) in patients (n = 28) with chronic renal parenchymal disease, in conditions of controlled sodium, potassium and phosphate intake. The levels of 5-hydroxyindolacetic acid (5-HIAA) were also evaluated in the same cohort of patients. Results: The patients were divided in two groups according to creatinine clearance (group 1, 39±6 ml/min/1.73 m², n = 14; group 2, 139±6 ml/min/1.73 m², n = 14). In patients of group 1, the urinary levels of L-DOPA, dopamine and DOPAC (in nmol/24 h) were significantly lower (60% reduction) than in patients of group 2 (L-DOPA, 134±36 vs. 308±51; dopamine, 759± 175 vs. 1,936± 117; DOPAC 2,595±340 vs. 7,938±833). Also, the urinary excretion of HVA in patients group 1 was significantly lower (40% reduction) than in patients of group 2 (17,434±2,455 vs. 27,179±2,271 nmol/24 h). By contrast, no significant difference was observed in daily urinary excretion of 5-HIAA between the two groups of patients (group 1, 27,280±3,721 nmol/day; group 2, 28,851±2,854 nmol/day). A positive linear relationship was found in these 28 patients between the creatinine clearance and the daily urinary excretion of L-DOPA (r = 0.64, p < 0.001), free dopamine (r = 0.83; p < 0.0001), DOPAC (r = 0.86; p < 0.0001) and HVA (r = 0.65; p < 0.002), but not with that of 5-HIAA (r = 0.14; ns). The U_{dopamine/L-DOPA} and U_{DOPAC/dopamine} ratios were found to be similar in both groups of patients, whereas the U_HVA/DOPAC ratios in patients of group 1 were found greater than in group 2 (p < 0.05). Conclusion: Patients suffering from chronic parenchymal disease with a compromised renal function present with a reduced activity of their renal dopaminergic system which correlates well with the degree of deterioration of renal function. The reduced urinary dopamine output in renal insufficiency is not attributable to enhanced metabolism of renal dopamine. We suggest that the urinary levels of DOPAC may represent a useful parameter for the assessment of renal dopamine synthesis.

5-Hydroxyindoleacetic acid (5-HIAA) and cortisol excretion as predictors of chemotherapy-induced emesis.

This study evaluated the relationship between prechemotherapy cortisol and 5-hydroxyindoleacetic acid (5-HIAA) excretion and chemotherapy-induced emesis. The urinary excretion of cortisol and the serotonin metabolite 5-HIAA in the night before chemotherapy administration were measured in 28 and 49 female patients receiving > 300 mg m-2 carboplatin. Vomiting and nausea were documented over a 3 day observation period. Lower basal cortisol excretion was significantly correlated with vomiting with or without nausea occurring within the observation period. 5-HIAA showed only a weak correlation with emesis on days 1-3, but low 5-HIAA excretion was correlated with a higher proportion of patients vomiting on days 2-3 following chemotherapy. Low basal cortisol excretion might be useful as a predictor for chemotherapy-induced emesis and therefore should be evaluated prospectively in future studies.

Changes in serotonin metabolism in pre-eclampsia

Several complications of pregnancy have been reported to be associated with alterations of serotonin (5-HT). This study describes the changes in 5-HT metabolism in patients with preeclampsia. Our examination findings should explain if there are elevated 5-HT and 5-HIAA concentrations in urine and serum of women with preeclampsia. On the other hand it should be proved if the observed chances are due to a decreased kidney function and if there is an important prognostic factor to detect asymptomatic preeclamptic patients. 5-HT and its main metabolite 5-hydroxy-indol-acetic acid (5-HIAA) was evaluated in serum and urine of 24 pregnant women with preeclampsia and of 27 pregnant women without preeclampsia in the last month of pregnancy, within 24 hours after delivery and at the fourth day post partum. Besides 5-HIAA was ascertained in 24-h urine from the 24th week of pregnancy until after delivery. 5-HIAA excretion increased continuously during pregnancy independently of whether the patients developed preeclampsia. A significant less increase and lower concentration of 5-HIAA pre and post partum were observed in preeclamptic patients when compared to non-preeclamptic patients. We noticed a remarkably lower 5-HIAA excretion and a higher concentration of 5-HT in women with preeclampsia. Preeclamptic patients demonstrate a lower decrease of 5-HIAA and a significantly greater increase of 5-HT than women without preeclampsia. These results could be explained by a decreased metabolism of 5-HT due to the placental MAO. The changes observed in our study are not due to a decreased kidney function because creatinine concentrations in women with and without preeclampsia were comparable. Our results indicate that 5-HIAA-/creatinine ratio might be an important prognostic factor.

Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction.

Sixty-four consecutive patients with disseminated midgut carcinoids were treated during an 8-year period according to a single clinical protocol aimed at aggressive tumor reduction by surgery alone or with subsequent hepatic artery embolization. All patients had markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels (581 +/- 79 micromol/24 h) and hormonal symptoms. Fourteen patients (22%) reached anatomic and biochemical cure by surgery alone. At follow-up, the mean 5-HIAA levels were still normal after 69.0 +/- 6. 2 months; two patients had died from unrelated causes. With the introduction of somatostatin receptor scintigraphy, subclinical disease was diagnosed in 7 of these 14 patients. Forty patients with bilobar hepatic disease underwent embolization in combination with octreotide. In this group, 5-HIAA levels were still reduced by 55% after 71 +/- 11 months of follow-up, and the 5-year survival was 56%, estimated from the total death hazard function. After embolization, two subgroups could be identified with marked differences in their long-term response to treatment. Ten patients were not embolized owing to complicating diseases. The 5-year survival for the entire series was 58%. A significantly increased risk of cardiovascular deaths was seen, which underlines the importance of total survival analysis in a disease with multiple hormonal effects. It is concluded that an active surgical approach must be recommended to patients with the midgut carcinoid syndrome. In patients with bilobar hepatic disease, embolization combined with octreotide treatment markedly reduced the 5-HIAA excretion and suggested a prolonged 5-year survival.

Serotonin metabolite excretion after postmenopausal estradiol therapy.

Serotonin, known for its beneficial action on mood and well-being, is also involved in cardiovascular functions. Thus the current work was undertaken to study the effect of hormone replacement therapy on serotonin turnover in postmenopausal women. Eighteen women received estradiol transdermally and 17 women estradiol valerate orally for 4 weeks. The serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA) was determined in the urine before, and after 2 and 4 weeks' estradiol treatment. With both administration routes estradiol produced a significant increase in urinary 5-HIAA excretion, greatest with transdermal estradiol after 28 days of treatment. The enhancement of serotonin turnover may contribute not only to an improvement of mood and well-being but also to a cardioprotective effect of estradiol observed after hormone substitution in postmenopausal women.

Acidic Catecholamine Metabolites and 5-Hydroxyindoleacetic Acid in Urine: The Influence of Diet

Concentrations of vanillylmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), vanillic acid (VA) and 5-hydroxyindoleacetic acid (5-HIAA) in urine from healthy subjects were determined by a high-performance liquid chromatography system with a mixed-mode (C18/anion-exchange) column and an 8-channel electrochemical detector, in order to study the influence of diet, diurnal variation and age. The urinary excretion of 5-HIAA increased significantly after eating banana, pineapple, tomato, kiwi fruit and walnut. An increase in the urinary excretion of DOPAC and HVA after eating banana and that of VA after taking vanilla was also noted. The urinary excretion of VMA was not significantly influenced by any of the foods examined. The urinary excretion of 5-HIAA in the first-morning urine increased beyond the upper limit of the reference value when banana was taken at 2000 h the previous day. The excretion of all metabolites in the second-morning urine in the fasting state was within respective reference ranges. Diurnal variation of the excretion of VMA, DOPAC, HVA and 5-HIAA in urine was relatively small, but that of VA was large. The concentrations (mmol/mol creatinine) of VMA, DOPAC, HVA, 5-HIAA and VA in the first-morning urine from healthy subjects increased from 7 days after birth to 1 year and then decreased to adult levels at 13 years of age.

Effect of cisplatin on the disposition of endogenous serotonin and its main metabolite, 5-hydroxyindole-3-acetic acid, in rats and dogs.

Emesis after the administration of cisplatin is a severe complication, and its treatment is an important problem clinically. Cisplatin forces the release of serotonin (5-HT) from enterochromaffin cells in the mucosa, and emesis occurs by the stimulation of 5-HT3 receptors. In this study, we established a simple and simultaneous method of determining 5-HT and its main metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), in plasma and urine by high performance liquid chromatography with electrochemical detection (HPLC-ECD), and determined the disposition of endogenous 5-HT and 5-HIAA after the administration of cisplatin in rats and dogs. In rats, we found no change in the plasma concentration of 5-HIAA after cisplatin administration, while a distinct increase was shown in the plasma concentration of 5-HT, but it was not significantly different from that of the control rats. The urinary excretion of 5-HIAA was also not different between the two groups. In dogs, we observed intense vomiting in all cisplatin treated dogs. However, we could not detect any change in the 5-HIAA or 5-HT level in the dog plasma. Furthermore, no significant difference in the urinary excretion of 5-HIAA was observed between the cisplatin group and the controls. From these results, the plasma concentration of 5-HT and the urinary excretion of 5-HIAA may not be suitable markers for the evaluation of emesis induced by anticancer drugs in dogs.

Serotonin mechanisms in chemotherapy-induced emesis in cancer patients.

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, nitrogen mustard and dacarbazine induce increases in urinary 5-hydroxyindoleacetic acid (5-HIAA) in parallel with the development of the period of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a modest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cisplatin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which is mostly resistant to 5-HT3 receptor antagonists (also known as 'delayed emesis'). This form of emesis is not associated with increases in urinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis inhibitor) inhibited cisplatin-induced emesis and cisplatin-induced increases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemotherapy-induced emesis. Serotonin released from enterochromaffin cells seems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5-HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cells by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplatin-induced emesis resistant to 5-HT3 receptor antagonists ('delayed emesis') is not mediated by serotonin released from enterochromaffin cells.

The role of serotonin as a mediator of emesis induced by different stimuli.

The aim of this work was to evaluate the impact of changes in serotonin metabolism on the pathophysiology of different types of emesis: pregnancy-induced emesis, emesis associated with inner-ear dysfunction, and cisplatin-induced emesis. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin, was measured in 13 women with pregnancy-induced emesis, 12 patients who had nausea and vomiting following inner-ear dysfunctions, 27 patients with cisplatin-induced emesis and a control group of 21 women. 5-HIAA was measured with a fluorescence polarization immunoassay (Abbott) and corrected for varying urine concentrations. Both patients with emesis associated with inner-ear dysfunction and patients with pregnancy-associated emesis showed a similar 5-HIAA excretion pattern compared with the control group. No correlation between intensity of nausea or vomiting and changes in 5-HIAA excretion could be detected. In patients receiving cisplatin, the 5-HIAA excretion increased rapidly within the 12 h following cisplatin administration and returned to baseline levels after 24 h. There was a parallel increase of 5-HIAA excretion and numbers of emetic episodes in the first 12 h, but delayed emesis was not associated with elevated 5-HIAA excretion. Our results provide evidence that serotonin is involved in the pathophysiology of cisplatin-induced acute emesis. Cisplatin-induced delayed emesis, pregnancy-associated emesis, and emesis due to inner-ear dysfunction are not associated with elevated levels of 5-HIAA excretion. The serotonin pathway probably represents only one of many different afferent mechanisms capable of initiating the emesis cascade.

CISPLATIN-INDUCED ALTERATIONS OF SEROTONIN METABOLISM IN PATIENTS WITH OR WITHOUT EMESIS FOLLOWING CHEMOTHERAPY

Serotonin (5-HT)(3) receptor antagonists are very effective in the control of cisplatin induced emesis. Nevertheless, a significant proportion of patients still experience emesis despite the use of these antiemetics. The aim of this study was to evaluate if cisplatin treated patients who vomit differ from patients who are completely protected from emesis with respect to measurable alterations of serotonin metabolism. We measured the urinary excretion of 5-hydroxyindole-acetic-acid (5-HIAA), the main metabolite of serotonin, in 24 patients with 42 courses of cisplatin containing chemotherapies. Patterns of 5-HIAA excretion were compared between patients with emesis and patients who are completely protected from vomiting. Three groups of patients without chemotherapy served as control. The first group did not receive any medication. The second and third group were given a single dose of ondansetron or metoclopramide. The median 5-HIAA/creatinine ratios in the control group ranged from 3.8 to 6.9 with a median of 6.2 (mu g 5-HIAA/mg creatinine). Neither ondansetron nor metoclopramide given without chemotherapy induced significant changes in 5-HIAA excretion patterns. 23 courses (55%) were associated with acute cisplatin-induced emesis. The median interval from the start of the cisplatin infusion to the peak 5-HIAA excretion was shorter in patients with acute emesis, but the cumulative amount of urinary 5-HIAA did not differ between patients with or without emesis. Patients who are efficiently protected from vomiting as well as patients who experience emesis show a comparable increase in urinary 5-HIAA following cisplatin therapy. The present study failed to show elevated 5-HIAA excretion levels occurring later than 24 hours following cisplatin administration. Nevertheless, patients experienced cisplatin-induced delayed emesis. Further studies are warranted to identify the pathomechanisms responsible for delayed emesis as well as that proportion of acute emesis which is refractory to 5-HT3 antagonism.

Association of biogenic amine metabolites with symptomatology in delusional (psychotic) and nondelusional depressed patients

1. 1. The levels of the main norepinephrine, serotonin, and dopamine metabolite excretion in the urine, MHPG, 5HIAA and HVA respectively, were measured in 84 patients with major depressive disorder, 34 delusional (psychotic) and 50 nondelusional (DSM-III-R criteria). 2. 2. Associations with the 17 items of the HDRS were evaluated using the multiple regression analysis model. In the delusional group, MHPG excretion was positively related to the scores in the items of depressed mood (p = 0.04), middle insomnia (p = 0.008) and genital symptoms (p = 0.001). 5HIAA excretion was negatively associated with late insomnia (p = 0.02), work and interests (p = 0.001) and genital symptoms (p = 0.007). HVA was positively related to agitation (p = 0.043). In the nondelusional group the only association found was between agitation and HVA excretion (p = 0.03).

Effect of pregnancy and labor on serotonin metabolism

Several complications of pregnancy have been reported to be associated with alterations of serotonin (5-hydroxytryptamine; 5-HT) metabolism. Reported data regarding changes of 5-HT metabolism in pregnancy are partially contradictory. The presented study tries to describe pregnancy-associated changes in 5-HT metabolism. Urine and blood samples were taken from 20 pregnant women 4 weeks before, within 24 hours and on the 4th day following delivery. 17 non-pregnant age-matched women served as controls. 5-HT and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) were analysed. We observed a continuously increasing production and excretion of unbound 5-HT and 5-HIAA during pregnancy. Four days after delivery 5-HT production returned to baseline levels, while excretion remained elevated. 5-HIAA excretion increased in pregnancy and return to baseline levels on the day following delivery. Increased 5-HT metabolism and excretion results in a decreased 5-HT serum concentration despite increased 5-HT production during pregnancy. Our results help to understand the contradictory observations of elevated 5-HT production on the one hand and decreased 5-HT activity during pregnancy on the other.

Assessment of renal dopaminergic system activity in the nitric oxide‐deprived hypertensive rat model

1. The present paper reports changes in the urinary excretion of dopamine, 5-hydroxytryptamine and amine metabolites in nitric oxide deprived hypertensive rats during long-term administration of NG-nitro-L-arginine methyl ester (L-NAME). Aromatic L-amino acid decarboxylase (AAAD) activity in renal tissues and the ability of newly-formed dopamine to leave the cellular compartment where the synthesis of the amine has occurred were also determined. 2. Twenty four hours after exposure to L-NAME, both systolic (SBP) and diastolic (DBP) blood pressure were increased by 20 mmHg; heart rate was slightly decreased. During the next 13 days both SBP and DBP increased progressively reaching 170 +/- 3 and 116 +/- 3 mmHg, respectively. 3. Baseline urinary excretion of L-DOPA, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) during the 4 day period of stabilization averaged 4.4 +/- 0.5, 13.8 +/- 0.3, 37.4 +/- 0.8, 180.0 +/- 2.7 and 206.1 +/- 6.7 nmol day-1, respectively. The urinary excretion of L-DOPA, dopamine and DOPAC, but not that of 3-MT and HVA, were increased from day 6-8 of L-NAME administration onwards (L-DOPA, up to 13.4 +/- 2.1; dopamine, up to 23.0 +/- 1.6; DOPAC, up to 62.8 +/- 3.7 nmol day-1). Baseline daily urinary excretion of 5-hydroxytryptamine and 5-hydroxyindolacetic acid (5-HIAA) averaged 73.5 +/- 1.1 and 241.7 +/- 5.4 nmol day-1, respectively. During the first week of L-NAME administration, the urinary excretion of both 5-hydroxytryptamine and 5-HIAA did not change significantly; however, as was found with dopamine and DOPAC, changes in the urinary excretion of 5-hydroxytryptamine were evident during the second week of L-NAME administration. 4. In experiments performed on homogenates of isolated renal tubules, the decarboxylation of L-DOPA to dopamine was dependent on the concentration of L-DOPA used (10 to 5000 microM) and saturable at 1000 microM. AAAD activity as determined in homogenates (Vmax, in nmol mg-1 protein h-1; Km in microM) was significantly (P < 0.01) higher in rats given L-NAME for 14 days (Vmax = 25 +/- 2; Km = 72 +/- 10) than in control rats (Vmax = 14 +/- 1; Km = 63 +/- 7), rats given L-NAME for 7 days (Vmax = 15 +/- 1; Km = 69 +/- 5) and rats given L-NAME plus L-arginine (Vmax = 13 +/- 1; Km = 60 +/- 3) for 14 days. 5. A considerable amount of the total dopamine formed from added L-DOPA in kidney slices escaped into the incubation medium. The application of the Michaelis-Menten equation to the net transport of newly-formed dopamine allowed the identification of a saturable (carrier-mediated transfer) and a non-saturable component (diffusion). No significant differences in the diffusional rate of transfer(0.14 +/- 0.02 micro mol-1) were observed between the four experimental groups. However, the saturable outward transfer of dopamine (Vmax, in micromol mg-1 protein h-1; Km in microM) was higher in control animals(Vmax= 2.3 +/- 0.2; Km = 568 +/- 67) than that in rats treated with L-NAME for 14 days (Vmax = 0.8 +/- 0.02;Km = 241 +/- 21), but similar to that observed in rats receiving L-NAME plus L-arginine (Vmax= 2.4+/- 0.2; Km= 618 +/- 61); the saturable dopamine outward rate of transfer in rats given L-NAME for 7days (Vmax = 3.9 +/- 0.2; Km = 1006 +/- 32) was higher than in controls.6. In conclusion, the present studies show that the hypertensive response resulting from the long-term administration of L-NAME is accompanied by an increased urinary excretion of dopamine and 5-hydroxytryptamine, which appears to follow an enhanced activity of renal AAAD. The observation that the increased AAAD activity can be reversed by the administration of L-arginine to L-NAME treated rats favours the view that the adaptational response which results in an enhanced AAAD activity probably involves a decrease in the generation of nitric oxide.

Clinical effects of octreotide compared to placebo in patients with gastrointestinal neuroendocrine tumours Report on a double‐blind, randomized trial

To compare the effect of octreotide with f placebo on symptoms, tumour marker and quality of life in patients with gastrointestinal neuroendocrine tumours and liver metastases. A blinded, placebo-controlled, cross-over study was performed. The number of flushing epidodes and diarrhoea episodes were registered for 1 week prior to the study and for the 8-week duration of the study. Quality of life and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured before the start, and at 4 and 8 weeks. Quality of life was registered with the Psychosocial Adjustment to Illness Scale (PAIS) and 5-HIAA measured by high-performance chromatography with electrochemical detection. 5-HIAA values exceeding 45 mumol 24 h-1 were considered to be elevated. The study was performed in a tertiary referral centre. Twelve patients were approached; eleven patients were included, with a mean age of 56.5 (range 30-72) years. The primary tumour originated from the small intestine in nine and from the pancreas in two patients. The main symptoms were diarrhoea, flushing and nausea. The 24-h excretion of 5-HIAA was increased in all patients. Patients were treated for 4 weeks with octreotide (100 micrograms) subcutaneously, twice daily, and for 4 weeks on placebo (octreotide vehicle) in random starting order. The main outcome measures were the number of episodes of the main clinical symptom(s) and 24-h 5-HIAA excretion. Octreotide lowered diarrhoea and flushing frequency significantly compared to placebo. 5-HIAA excretion was reduced during treatment with the active drug. Two domains of the PAIS were significantly improved, indicating that the reduction of tumour marker and symptoms were clinically important. The clinical effect of octreotide on symptoms in patients with neuroendocrine tumours was demonstrated in a controlled, prospective trial.