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Average concentration time profile of plasma adrenocorticotrophic hormone (acth) with sd error bars (closed circle: Placebo; open circle: Incremental infusion; open square: Bolus infusion)
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A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, fo...
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AIM
To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide (HO/CO) pathway in the constipating effects of granisetron.
METHODS
For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous (sc)], zinc protoporphyrin IX [Zn...
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing...
The aim of this study was to assess the non-inferiority of 1 mg to 3 mg granisetron (GRN) injection for the treatment of acute chemotherapy-induced nausea and vomiting (CINV) and to evaluate the tolerability of GRN given at 1 mg in Japanese cancer patients.
Patients with cancer receiving highly emetogenic chemotherapy were enrolled in this single-b...
Citations
... 2-7 5-HTP is also reported as a challenge test to examine central serotonergic function, with cortisol and prolactin release used as a measure of response, as well as the excretion of the metabolite 5-hydroxy-indoleacetic acid. [8][9][10][11][12] In previous studies, we have demonstrated reproducible, concentration-dependent pharmacodynamic effects with acceptable variability associated with a serotonergic function test in healthy volunteers using 5-hydroxytryptophan (5-HTP). 8,9 Carbidopa and granisetron were co-administrated with 5-HTP. ...
... [8][9][10][11][12] In previous studies, we have demonstrated reproducible, concentration-dependent pharmacodynamic effects with acceptable variability associated with a serotonergic function test in healthy volunteers using 5-hydroxytryptophan (5-HTP). 8,9 Carbidopa and granisetron were co-administrated with 5-HTP. Carbidopa prevented the peripheral conversion of 5-HTP to 5-hydroxytryptamine (5-HT) which would preclude brain penetration, while granisetron limited serotonergic side-effects such as gastro-intestinal stimulation and vomiting without influencing the neuroendocrine response or 5-HTP pharmacokinetics. ...
... Carbidopa was administrated to prevent peripheral carboxylation which can stabilize the PK of 5-HTP and granisetron was administrated as an antiemetic to reduce the systemic side-effects of 5-htp. 8,9 The sampling time started before the administration of 5-HTP and finished 5 to 9 hours after 5-HTP administration. The 5-HTP challenge trial designs scheme were separately described in previous publications and summarized in In total, 35 healthy male volunteers participated in these studies. ...
This research was planned to build a Pharmacokinetic/Pharmacodynamic (PK/PD) model of 5‐hydroxytryptophan (5‐HTP) challenge study including a circadian rhythm component of cortisol and to predict serum cortisol based on saliva cortisol. Data from three 5‐HTP challenge studies in healthy volunteers were collected. Serum 5‐HTP, saliva, and serum cortisol were sampled as PK and PD marker. The population PK/PD modeling approach was applied. A baseline model of serum cortisol was built to assess the circadian rhythm before a pharmacodynamic model was used to evaluate the drug effect of the 5‐HTP on cortisol. Finally, linear and power function relationships were tested to predict serum cortisol based on saliva cortisol. The PK of 5‐HTP could be described using a one‐compartment model with a transit compartment. The typical value for clearance was 20.40 L h−1 and showed inter‐study variability. A cosine function was chosen and properly described the circadian rhythm of serum cortisol. A linear approximation model was applied to fit the 5‐HTP PD effect on cortisol data with a slope of 4.16 ng mL−1 h. A power function provided a better description than a linear function to relate the saliva and serum cortisol. In conclusion, a circadian rhythm component was built in the PK/PD model of the 5‐HTP challenge test which could better improve the understanding of the stimulating effect on HPA with cortisol change. After the 5‐HTP challenge, saliva cortisol correlated well with serum cortisol and was predictable by a population PK‐PD model.
... RS-fMRI effects of selective 5-HT 3 receptor antagonists as granisetron are lacking, but need to be taken into consideration when interpreting the results [Jacobs and Azmitia, 1992]. However, intolerability to our intensive study procedures would have been undesirable [Jacobs et al., 2010a] and vomiting might have altered brain connectivity as well. To reduce nausea, we also decided to Abbreviations: L, left; R, right; M, midline; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex. ...
Psychopharmacological research, if properly designed, may offer insight into both timing and area of effect, increasing our understanding of the brain's neurotransmitter systems. For that purpose, the acute influence of the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was repeatedly measured in 12 healthy young volunteers with resting state functional magnetic resonance imaging (RS-fMRI). Eighteen RS-fMRI scans were acquired per subject during this randomized, double blind, placebo-controlled, crossover study. Within-group comparisons of voxelwise functional connectivity with 10 functional networks were examined (P < 0.05, FWE-corrected) using a non-parametric multivariate approach with cerebrospinal fluid, white matter, heart rate, and baseline measurements as covariates. Although both compounds did not change cognitive performance on several tests, significant effects were found on connectivity with multiple resting state networks. Serotonergic stimulation primarily reduced connectivity with the sensorimotor network and structures that are related to self-referential mechanisms, whereas galantamine affected networks and regions that are more involved in learning, memory, and visual perception and processing. These results are consistent with the serotonergic and cholinergic trajectories and their functional relevance. In addition, this study demonstrates the power of using repeated measures after drug administration, which offers the chance to explore both combined and time specific effects. Hum Brain Mapp, 2016. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.
... This coincides with a non-significant trend towards experienced nausea on the VAS. Granisetron was added to prevent nausea and vomiting (Jacobs et al., 2010a), which as a side effect of sertraline could have altered the network responses or reduced the tolerability of the procedures (Jacobs et al., 2010b). To balance the study, granisetron was also administrated on placebo days. ...
... On the other hand, the given mechanism favors free tryptophan transport to the brain as well as the synthesis and 5-HT release (Blomstrand et al. 2009; Newsholme and Blomstrand 2006). 5-HTP shows high ability to permeate through blood–brain barrier (Jacobs 2010). It is connected with the compound structural build and relatively short serotonin half-life. ...
Collagens are major structural proteins of tendons, ligaments and other components of musculoskeletal tissues. Rare mutations in many of the genes, which encode for the collagen α-chains, result in serious musculoskeletal disorders, highlighting the importance of this protein family in the normal structure and function of musculoskeletal tissues. Since these rare mutations cause severe disorders, it has been proposed that a lack of biological redundancy exists within the collagen fibril, and that collagen-encoding genes are therefore ideal candidates for association with less severe exercise-related traits. This review identifies a number of collagen
gene variants which are associated with various exercise-related traits. Based on the evidence outlined in this review, we propose that a general genetic continuum exists for collagen genes and their associated traits. At one end of this general continuum model, a single mutation within one or more collagen genes will result in severe Mendelian disorders. At the other end of the continuum, functional variants within these collagen genes collectively contribute to the aetiology of anomalous multifactorial connective tissue traits, which arise as
a result of the interaction of genetic and non-genetic factors which modulate physiological responses to environmental stimuli.
... We also determined whether inflammation was reduced by supplementation with 5-HTP during the OVA challenge phase (after OVA sensitization) (Fig. 1D). The level of 5-HTP in the rodent diets (Fig. 1B) was calculated to be equivalent to that for human consumption of 200 mg 5-HTP/100 pound person/day because clinical studies with 5-HTP supplementation use 100 -300 mg 5-HTP/ person/day (12,45,50,60,76,101,103). We confirmed the 5-HTP concentration in the diet by HPLC/ECD (Fig. 1B). ...
Clinical reports indicate that patients with allergy/asthma commonly have associated symptoms of anxiety/depression. Anxiety/depression can be reduced by 5-hydroxytryptophan (5-HTP) supplementation. However, it is not known whether 5-HTP reduces allergic inflammation. Therefore, we determined whether 5-HTP supplementation reduces allergic inflammation. We also determined whether 5-HTP decreases passage of leukocytes through the endothelial barrier by regulating endothelial cell function. For these studies, C57BL/6 mice were supplemented with 5-HTP, treated with ovalbumin fraction V (OVA), house dust mite (HDM) extract, or IL-4, and examined for allergic lung inflammation and OVA-induced airway responsiveness. To determine whether 5-HTP reduces leukocyte or eosinophil transendothelial migration, endothelial cells were pretreated with 5-HTP, washed and then used in an in vitro transendothelial migration assay under laminar flow. Interestingly, 5-HTP reduced allergic lung inflammation by 70-90% and reduced antigen-induced airway responsiveness without affecting body weight, blood eosinophils, cytokines, or chemokines. 5-HTP reduced allergen-induced transglutaminase 2 (TG2) expression and serotonylation (serotonin conjugation to proteins) in lung endothelial cells. Consistent with the regulation of endothelial serotonylation in vivo, in vitro pretreatment of endothelial cells with 5-HTP reduced TNF-α-induced endothelial cell serotonylation and reduced leukocyte transendothelial migration. Furthermore, eosinophil and leukocyte transendothelial migration was reduced by inhibitors of transglutaminase and by inhibition of endothelial cell serotonin synthesis, suggesting that endothelial cell serotonylation is key for leukocyte transendothelial migration. In summary, 5-HTP supplementation inhibits endothelial serotonylation, leukocyte recruitment, and allergic inflammation. These data identify novel potential targets for intervention in allergy/asthma.
... Alternatively, serotonergic (precursor) agents can be used as endogenous corticotrophinergic stimulants of the HPA axis Gijsman et al., 1998;Gijsman et al., 2002;Smarius et al., 2008). A serotonergic function test consisting of 5-hydroxytryptophan (5-HTP) has been developed for this purpose (Jacobs et al., 2010a). 5-HTP is the direct precursor of serotonin (5-HT) and is centrally converted into 5-HT. ...
... The 5-HTP function test was administered according to the procedure described previously (Jacobs et al., 2010a;Smarius et al., 2008). It consisted of the administration of carbidopa 100 mg (at t = −180 min to reduce peripheral metabolism of 5-HTP) and granisetron 2 mg (at t = − 60 min to prevent nausea and vomiting), followed by a single oral dose of 5-HTP 200 mg (at t = 0 min) and a repeat dose of carbidopa 50 mg (at t = 180 min). ...
... caused maximal ACTH concentration of 59.2 ng/L and maximal cortisol levels of 196.4 μg/L (Jacobs et al., 2010c). Also, the present cortisol levels approached those attained previously with (near-maximally tolerated) serotonergic (170 to 230 μg/L) (Jacobs et al., 2010a;Smarius et al., 2008) and corticotrophinergic (210 to 230 μg/L) (Dinan and Scott, 2005;Scott et al., 1999) function tests. Taken together, ACTH and cortisol release induced by 200 mg 5-HTP is reconcilable with corticotrophinergic activation of the HPA axis. ...
The synthetic vasopressin (AVP) analogue desmopressin (dDAVP) has been used as pharmacological function test to quantify vasopressinergic co-activation of the hypothalamus-pituitary-adrenal (HPA) axis in the past. Such exogenous vasopressinergic stimulation may induce confounding cardiovascular, pro-coagulatory and anti-diuretic effects and low endogenous corticotrophin-releasing-hormone (CRH) levels may limit its potential to reliably assess co-activation. Alternatively, the dopamine-2-(D2)-antagonist metoclopramide is believed to induce co-activation indirectly by releasing endogenous AVP. We investigated this indirect co-activation with metoclopramide under conditions of low and enhanced endogenous CRH release in healthy volunteers. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in 12 healthy males. CRH release was induced by administering an oral 5-hydroxytryptophan (5-HTP) 200 mg function test. Co-activation was investigated by administering metoclopramide 10mg intravenously around the expected maximal effect of 5-HTP. The neuroendocrine effects were compared to those of metoclopramide alone, the 5-HTP test alone and matching placebo. Metoclopramide safely induced HPA-axis activation by itself, and potently synergized 5-HTP-induced corticotrophinergic activation of the HPA axis. These findings are indicative of vasopressinergic co-activation and suggest a role for metoclopramide as a practical function test for co-activation of the HPA axis. However, its application will be hampered pending clarification of the exact pharmacological mechanism by which metoclopramide induces co-activation of the HPA axis.
Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HTP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NAA) and creatine using 7-Tesla (7T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers.
A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4h and MRS scans at 7T were performed every 30min over 3h measuring Glx:Creatine, Chol:Creatine and NAA:Creatine ratios.
In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NAA levels over 180min but induced a significant decrease of Glx at 60min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E(max) of 60.2ng/L at 80min followed by cortisol with an E(max) of 246.4ng/mL at 110min.
The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area.
