Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.
PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved. (+info)
The role of free serum tryptophan in the biphasic effect of acute ethanol administration on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid.
1. Acute administration of ethanol exerts a biphasic effect on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid. Both effects are associated with corresponding changes in the availability of circulating free tryptophan. 2. The initial increases in the above concentrations are prevented by ergotamine, are unaltered by allopurinol and are potentiated by theophylline, whereas the later decreases are prevented by both ergotamine and allopurinol. 3. It is suggested that the initial enhancement by ethanol of brain tryptophan metabolism is caused by catecholamine-mediated lipolysis followed by displacement of protein-bound serum tryptophan, whereas the activation of liver tryptophaan pyrrolase, which is produced by the same mechanism, leads to the later decreases in the brain concentrations of tryptophan and its metabolites. 4. The initial effects of ethanol can be reproduced by an equicaloric dose of sucrose, and a comparison of the two treatments alone could therefore be misleading. 5. The effects of ethanol on liver and brain tryptophan metabolism have also been examined in mice, and a comparison of the results with those previously reported suggests that the ethanol effects are strain-dependent. (+info)
Spinal reflexes and the concentrations of 5-HIAA, MHPG, and HVA in lumbar cereborspinal fluid after spinal lesions in man.
Descending bulbospinal pathways that employ specific neurotransmitter substances are known to be capable of modulating segmental reflex activity in the experimental animal. To determine whether this might also occur in man correlations have been sought between the activity in spinal reflex pathways and the lumbar cerebrospinal fluid (CSF) concentrations of 5-hydroxyindolacetic acid (5-HIAA), 3 methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) in 12 patients with complete or virtually complete spinal lesions. The concentrations of 5-HIAA and MHPG in lumbar CSF ARE REDUCED AFTER COMPLETE OR VIRTUALLY COMPLETE SPINAL LESIONS IN MAN. This may occur within 18 days of the lesion. MHPG concentrations appear to be inversely related to the level of the lesion. The HVA concentration in lumbar CSF is reduced when there is obstruction of the CSF pathways. No relationship could be demonstrated between the concentrations of 5-HIAA or MHPG in lumbar CSF and the activity in the spinal monosynaptic pathway (estimated from the proportion of the motoneurone pool activated by the Achilles tendon reflex or H reflex) or the activity of a spinal inhibitory mechanism (estimated by the degree of vibratory inhibition of the monosynaptic reflex). Patients with a tonic vibration reflex (TVR) tended to have higher MHPG levels. There appeared to be an association between low CSF HVA and enhanced vibratory inhibition of the monosynaptic reflex in the nine patients whose spinal lesions were complete. (+info)
Increased dopaminergic and 5-hydroxytryptaminergic activities in male rat brain following long-term treatment with anabolic androgenic steroids.
1. The effects of treating groups of rats with four different anabolic androgenic steroids (AAS) (testosterone, nandrolone, methandrostenolone, and oxymetholone) on 5-hydroxytryptamine (5-HT) and dopamine (DA) neurones in different brain regions were examined. The AAS was injected six times with 1 week's interval and the rats were sacrificed 2 days after the final injection. 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. The effect on DA and 5-HT synthesis rate was analysed as the accumulation of 3,4-dihydroxyphenyl-alanine (DOPA) and 5-hydroxytryptophan (5-HTP), respectively, after inhibition of the amino acid decarboxylase with NSD-1015 (3-hydroxy-benzylhydrazine dihydrochloride). Additionally, the monoamine oxidase (MAO) activity was analysed in the hypothalamus. 2. The DOPAC + HVA/DA ratio was increased in the striatum in all treatment groups. However, the synthesis rate of DA was significantly increased only in the methandrostenolone treated group. 3. The 5-HIAA/5-HT ratio was increased in all treatment groups in the hippocampus, in the frontal cortex in the methandrostenolone-treated animals and in the hypothalamus in the testosterone- and oxymetholone-treated rats, while the 5-HT synthesis rate was not affected by the AAS-treatments. 4. The MAO-A activity was increased in the oxymetholone-treated rats while the other treatment groups were unaffected. The MAO-B activity was not changed. 5. The results indicate that relatively high doses of AAS increase dopaminergic and 5-hydroxytryptaminergic metabolism in male rat brain, probably due to enhanced turnover in these monaminergic systems. (+info)
Cerebrospinal fluid monoaminergic metabolites differ in wild anubis and hybrid (Anubis hamadryas) baboons: possible relationships to life history and behavior.
The article reports monoaminergic metabolite [homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG)], values from the cerebrospinal fluid (CSF) of 27 wild baboons (Papio hamadryas) aged 40 to 140 months. Animals were either anubis, or anubis with hamadryas admixture; males of the latter subspecies generally have a reduced tendency to disperse from their natal groups. Overall, the values and interrelationships among the CSF monoamine metabolites resembled data reported from closely related, captive-housed animals. For example, age was significantly correlated with HVA concentrations (r = -60, p < .05), but not with the other metabolites. Notably, males characterized by hamadryas admixture had significantly higher concentrations of HVA, 5-HIAA, and MHPG (p < .05, respectively), a result possibly driven by differences in serotonergic activity. These data provide initial evidence that variation in central monoaminergic activity, as indicated by CSF monoamine metabolite concentrations, may reflect differences in behavior and life history that have taxonomic and, perhaps, evolutionary significance. (+info)
Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin.
Alcohols and aldehydes in the metabolic pathways of ethanol and serotonin are substrates for alcohol dehydrogenases (ADH) of class I and II. In addition to the reversible alcohol oxidation/aldehyde reduction, these enzymes catalyse aldehyde oxidation. Class-I gammagamma ADH catalyses the dismutation of both acetaldehyde and 5-hydroxyindole-3-acetaldehyde (5-HIAL) into their corresponding alcohols and carboxylic acids. The turnover of acetaldehyde dismutation is high (kcat = 180 min-1) but saturation is reached first at high concentrations (Km = 30 mm) while dismutation of 5-HIAL is saturated at lower concentrations and is thereby more efficient (Km = 150 microm; kcat = 40 min-1). In a system where NAD+ is regenerated, the oxidation of 5-hydroxytryptophol to 5-hydroxyindole-3-acetic acid proceeds with concentration levels of the intermediary 5-HIAL expected for a two-step oxidation. Butanal and 5-HIAL oxidation is also observed for class-I ADH in the presence of NADH. The class-II enzyme is less efficient in aldehyde oxidation, and the ethanol-oxidation activity of this enzyme is competitively inhibited by acetate (Ki = 12 mm) and 5-hydroxyindole-3-acetic acid (Ki = 2 mm). Reduction of 5-HIAL is efficiently catalysed by class-I gammagamma ADH (kcat = 400 min-1; Km = 33 microm) in the presence of NADH. This indicates that the increased 5-hydroxytryptophol/5-hydroxyindole-3-acetic acid ratio observed after ethanol intake may be due to the increased NADH/NAD+ ratio on the class-I ADH. (+info)
Sensitization to the effects of tumor necrosis factor-alpha: neuroendocrine, central monoamine, and behavioral variations.
Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 microg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-alpha were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 microgram) 14-28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1-7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected by elevated accumulation of 3-methoxy-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alpha reexposure at the 1 d interval was associated with a pronounced sensitization-like effect, which was not apparent at longer intervals. Evidently, systemic TNF-alpha proactively influences the response to subsequent treatment; however, the nature of the effects (i.e., the behavioral, neuroendocrine, and central transmitter alterations) vary over time after initial cytokine treatment. It is suggested that the sensitization may have important repercussions with respect to cognitive effects of TNF-alpha and may also be relevant to analyses of the neuroprotective or neurodestructive actions of cytokines. (+info)
Altered daily rhythms of brain and pituitary indolamines and neuropeptides in long-term hypoxic rats.
To determine whether sustained hypoxia alters daily rhythms in brain and pituitary neurotransmitters, the daily variations in vasoactive intestinal peptide-like immunoreactivity (VIP-LI), neuropeptide Y-like immunoreactivity (NPY-LI), serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) content were determined in discrete brain regions, pineal gland and anterior pituitary of hypoxic (10% O(2); 14 days) and normoxic rats. Hypoxia suppressed daily variations in VIP-LI in the suprachiasmatic nuclei (SCN) and the anterior pituitary, enhanced the daily rhythmicity in serotonergic elements of the caudal part of the dorsomedial medulla oblongata (DMMc), and even induced daily variations in NPY-LI in the DMMc as well as in the ventrolateral medulla oblongata. In addition, punctual alterations in the rhythmicity of 5-HT and 5-HIAA in the pineal gland and of plasma corticosterone were observed in hypoxic rats. Thus results of this study indicate that a permanent nonphotic stimulus, such as sustained hypoxia, may affect the functioning of the internal clock located in the SCN and may alter the daily rhythmicity in neurotransmitter content of some brain nuclei and the pituitary gland. (+info)