Tryptophan Hydroxylase Inhibitor Research Articles

Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.

A phase 2, open-label, safety and efficacy study of telotristat ethyl plus first-line chemotherapy in patients with advanced biliary tract cancer.

472 Background: Patients (pts) with unresectable biliary tract cancer (BTC) have a poor prognosis. In preclinical models of cholangiocarcinoma (CCA) telotristat ethyl (TE), a tryptophan hydroxylase inhibitor that reduces production of serotonin, enhanced the antiproliferative effects of gemcitabine and cisplatin (GC) chemotherapy. This trial assessed the safety and efficacy of adding TE to GC chemotherapy in pts with advanced BTC. Methods: This was a Phase 2 open-label study. Eligible pts had unresectable, locally advanced, or metastatic BTC, were treatment naïve and had plans to initiate GC chemotherapy. On Day 1, pts received Gem 1000mg/m2 and Cis 25mg/m2 with TE 250 mg orally three times daily (TID) for 7 days. Thereafter, pts received TE 500 mg TID continuously plus GC therapy on days 1 and 8 of each 21-day cycle. The study comprised of 2 stages: stage 1 would enroll 20 patients with a safety run-in cohort in the first 6 pts to monitor safety and tolerability of TE + GC treatment for 21 days. Stage 2 would enroll 33 patients if no significant/unresolved grade 3 or higher toxicities related to study drug occurred in stage 1. The primary endpoint was 6-month (mo) progression free survival (PFS) rate according to RECIST 1.1. If 60% of pts (≥34) in the safety population were alive and progression free at 6-mos, the study was considered successful. Secondary endpoints included overall response rate (ORR) and disease control rate (DCR). Restaging occurred every 9 weeks using RECIST 1.1 and toxicities were graded using CTCAE v 5.0. Results: Between 2019 and 2021, fifty-three pts were enrolled across 12 study sites and comprised the safety population. The majority of pts were female (62.3%) and median age was 66 yrs (range 33 to 79). Baseline mean plasma 5-HIAA was 11.1 µg/L (ULN defined as &gt;10.8 µg/L). Thirty-one pts (58.5%) had plasma 5-HIAA levels ≤ULN and 22/53 (41.5%) had 5-HIAA levels &gt;ULN. Majority of pts had metastatic BTC (85%) and liver was the most common primary tumor site (66%). The 6-month PFS rate was 22.6% (12/53). Based on blinded independent central review, the ORR was 13.2% and DCR was 62.3%. Mean reduction in plasma 5-HIAA at 6 mos was -1.735 µg/L (SD 8.69) in 24 patients with available data. There was no difference in 6-mo PFS rate based on pts baseline 5-HIAA status; 58% (14/24) pts had ≥30% decrease from baseline in 5-HIAA, however there was no correlation with 6-month PFS. The most common TE related TEAEs were constipation (43.4%), nausea (28.3%) and fatigue (28.3%). Conclusions: The study did not achieve its primary endpoint of 60% of patients on TE plus GC chemotherapy being alive and progression free at 6 months. TE did reduce 5-HIAA levels in a subset of pts; however, this did not correlate to improved clinical outcomes. No significant safety issues noted with TE in combination with GC chemotherapy. Clinical trial information: NCT03790111 .

Use of perioperative telotristat in a patient with carcinoid heart disease.

Carcinoid heart disease is a rare complication of carcinoid syndrome, resulting in right-sided valvular heart disease and subsequent heart failure due to long-term exposure to vasoactive substances. The management of this condition is complex, often requiring surgical intervention. Current perioperative regimens entail the use of prophylactic somatostatin analogs to prevent carcinoid crisis; however, regimens vary widely among practitioners and evidence supporting their efficacy in this clinical setting is mixed. This case report describes the perioperative management of a 65-year-old man with carcinoid heart disease requiring tricuspid and pulmonary valve replacement surgery. As an adjunct to somatostatin analog therapy, the novel tyrosine hydroxylase inhibitor, telotristat, was initiated preoperatively. This combination resulted in normalization of preoperative urinary 5-HIAA levels. The patient successfully underwent tricuspid and pulmonic valve replacement without evidence of carcinoid crisis. This clinical case is the first published documenting the use of telotristat in the perioperative period in a patient with carcinoid syndrome and carcinoid heart disease and was associated with a good long-term outcome despite the high-risk nature of the case. Carcinoid crisis is a life-threatening complication of carcinoid syndrome, resulting in hemodynamic instability, bronchospasm, and arrhythmia. Cardiac surgical patients with carcinoid syndrome present a unique challenge as they are subject to physiologic conditions and medications which can potentiate intraoperative carcinoid crisis. Perioperative management of patients with carcinoid syndrome currently entails the use of prophylactic somatostatin analogs; however, these agents do not prevent carcinoid crisis in all cases. Telotristat, a tryptophan hydroxylase inhibitor, shows promise as an adjunctive therapy to somatostatin analogs to reduce the risk of intraoperative carcinoid crisis.

Structure-Based Design of Xanthine-Imidazopyridines and -Imidazothiazoles as Highly Potent and In Vivo Efficacious Tryptophan Hydroxylase Inhibitors.

Tryptophan hydroxylases catalyze the first and rate-limiting step in the biosynthesis of serotonin, a well-known neurotransmitter that plays an important role in multiple physiological functions. A reduction of serotonin levels, especially in the brain, can cause dysregulation leading to depression or insomnia. In contrast, overproduction of peripheral serotonin is associated with symptoms like carcinoid syndrome and pulmonary arterial hypertension. Recently, we developed a class of TPH inhibitors based on xanthine-benzimidazoles, characterized by a tripartite-binding mode spanning the binding sites of the cosubstrate pterin and the substrate tryptophan and by chelation of the catalytic iron ion. Herein, we describe the structure-based development of a second generation of xanthine-imidiazopyridines and -imidazothiazoles designed to inhibit TPH1 in the periphery while preventing the interaction with TPH2 in the brain. Lead compound 32 (TPT-004) shows superior pharmacokinetic and pharmacodynamic properties as well as efficacy in preclinical models of peripheral serotonin attenuation and colorectal tumor growth.

Methyleugenol Has an Antidepressant Effect in a Neuroendocrine Model: In Silico and In Vivo Evidence.

Major depressive disorder is a severe mood disorder characterized by different emotions and feelings. This study investigated the antidepressant activity of the phenylpropanoid methyleugenol (ME) in adult female mice exposed to a stress model induced by dexamethasone. The animals were randomly divided into groups containing eight animals and were pre-administered with dexamethasone (64 μg/kg subcutaneously). After 165 and 180 min, they were treated with ME (25, 50 and 100 mg/kg intraperitoneally) or imipramine (10 mg/kg intraperitoneally) after 45 min and 30 min, respectively; they were then submitted to tests which were filmed. The videos were analyzed blindly. In the tail suspension test, ME (50 mg/kg) increased latency and reduced immobility time. In the splash test, ME (50 mg/kg) decreased grooming latency and increased grooming time. In the open field, there was no statistical difference for the ME groups regarding the number of crosses, and ME (50 mg/kg) increased the number of rearing and time spent in the center. Regarding in silico studies, ME interacted with dopaminergic D1 and α1 adrenergic pathway receptors and with tryptophan hydroxylase inhibitor. In the in vivo evaluation of the pathways of action, the antidepressant potential of ME (50 mg/kg) was reversed by SCH23390 (4 mg/kg intraperitoneally) dopaminergic D1 receptor, Prazosin (1 mg/kg intraperitoneally) α1 adrenergic receptor, and PCPA (4 mg/kg intraperitoneally) tryptophan hydroxylase inhibitor. Our findings indicate that ME did not alter with the locomotor activity of the animals and shows antidepressant activity in female mice with the participation of the D1, α1 and serotonergic systems.

Anxiolytic-like action of 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) in mice: A possible contribution of the serotonergic system

Anxiety disorders, characterized by high prevalence rates, cause psychiatric disabilities and are related to impairments in serotoninergic system function. Frequent anxiety recurrence, resistance, and drug adverse effects have driven searches for new therapies. We initially evaluated the anxiolytic-like activity of 3-selanyl-benzo[b]furan compounds (SeBZF1–5) (50 mg/kg, i.g.) in male Swiss mice using the light-dark test (LDT). The compound 3-((4-methoxyphenyl)selanyl)-2-phenylbenzofuran (SeBZF3) exhibited anxiolytic-like activity. SeBZF3 anxiolytic-like effects were also observed in the novelty-suppressed feeding test (NSFT) (50 mg/kg) and elevated plus-maze test (EPMT) (25 and 50 mg/kg). In the EPMT, anxiolytic-like effects of SeBZF3 (50 mg/kg) were abolished by pretreatment with p-chlorophenylalanine, a selective tryptophan hydroxylase inhibitor (100 mg/kg, i.p. for 4 days), suggesting the involvement of serotonergic mechanisms. Furthermore, we conducted experiments to investigate the synergistic effects of SeBZF3 subeffective doses (5 mg/kg, i.g.) in combination with fluoxetine (a selective serotonin reuptake inhibitor, 5 mg/kg, i.p.) or buspirone (a partial agonist of the 5-HT1A receptor, 2 mg/kg, i.p.). This coadministration resulted in pronounced synergistic effects. We also examined the effects of repeated oral treatment with SeBZF3 at doses of 1 and 5 mg/kg over 14 days and both reduced anxiety signals. In vitro and ex vivo findings revealed that SeBZF3 inhibited cerebral MAO-A activity. These findings collectively imply the potential involvement of serotonergic mechanisms in the anxiolytic-like activity of SeBZF3 in mice. These data offer contributions to the research field of organoselenium compounds and anxiolytics, encouraging the broadening of the search for new effective drugs while offering improved side effect profiles.

Effect of Prolonged Exposure to Short Daylight and a Tryptophan Hydroxylase Inhibitor on the Behavior and Brain Serotonin System in Danio rerio.

We studied the effect of reduced tryptophan hydroxylase (TPH) activity and short daylight exposure on the behavior and the 5-HT system of the brain in D. rerio. Male and female D. rerio were exposed for 30 days to standard (12:12 h light:dark) and short (4:20 h light:dark) photoperiods in the presence or absence of TPH inhibitor (p-chlorophenylalanine, pCPA, 5 mg/liter). On day 31, the fish behavior in the "novel tank diving" test, their sex and body weight were determined, and the levels of pCPA, 5-HT, and its metabolite 5-HIAA were measured by HPLC; the levels of the key genes encoding metabolism enzymes (Tph1a, Tph1b, Tph2, and Mao) and receptors of 5-HT (Htr1aa, Htr2aa) were assessed by real-time PCR with reverse transcription. The short daylight exposure caused masculinization of females, reduced body weight, and motor activity in the "novel tank diving" test, but did not affect the 5-HT system of the brain. Long-term pCPA treatment had no effect on sex and body weight, significantly reduced the 5-HIAA level, but increased Tph1a and Tph2 gene expression in the brain. No effects of the interaction of short daylight and pCPA exposure on the sex, body weight, behavior, and 5-HT system of the brain were found. Thus, a moderate decrease in TPH activity cannot potentiate the negative effects of short daylight exposure on the sex, body weight, behavior, and 5-HT system of D. rerio.

Abstract 480: Enhancing chemotherapy response by telotristat ethyl, an inhibitor of tryptophan hydroxylase involved in serotonin synthesis, in cholangiocarcinoma

Abstract Objective: Cholangiocarcinoma (CCA) is a highly aggressive biliary tract cancer (BTC). CCAs are divided into three subtypes: intrahepatic (iCCA, 10-20%), perihilar (pCCA, 50-60%) or distal (dCCA, 20-30%). CCA has a very poor prognosis with a 5-year survival rate of 5-15%. The majority of CCA patients (~80%) present with unresectable disease where gemcitabine plus cisplatin (GemCis) is the standard treatment with a median survival of 14 months. Nanoparticle albumin-bound (nab) paclitaxel (NPT) is an approved treatment for breast cancer, NSCLC and pancreatic cancer that is under clinical investigation for several solid tumors including CCA. Increased accumulation and secretion of serotonin have been reported to support its oncogenic activity in CCA. Telotristat ethyl (TE) is an inhibitor of tryptophan hydroxylase 1 (TPH1) that mediates peripheral serotonin synthesis. We investigated the therapeutic efficacy of TE in combination with standard chemotherapies in preclinical models of CCA. Methods: Tumor growth studies were performed in subcutaneous cell-derived xenografts (CDX) using human CCLP-1 cells (iCCA), TFK-1 cells (dCCA), SNU-1196 cells (pCCA) in NOD/SCID mice, and in patient-derived xenografts (PDX) in NSG mice. Animal survival studies were performed in peritoneal dissemination xenografts in NOD/SCID mice using iCCA CCLP-1 cells. Intratumoral proliferation and serotonin levels were determined by immunohistochemistry (IHC). Results: In peritoneal dissemination xenografts, animal survival was markedly enhanced by NPT (60%), while TE (11%) or GemCis (9%) had a marginal effect. The combination of TE with GemCis (26%) or NPT (68%) exhibited a further increase in animal survival. In iCCA xenografts, tumor growth inhibition by TE was 53%, and NPT (69%) caused greater inhibition than GemCis (53%). In dCCA xenografts, tumor growth inhibition by TE was 51%, and NPT (56%) was more effective than GemCis (37%). In pCCA xenografts, tumor growth reduction by TE, NPT and GemCis was 41%, 67% and 58%. In all three cell-derived xenografts, TE combination with chemotherapy demonstrated an improved tumor growth inhibition effect (range: 67-90%). In PDX studies, TE markedly inhibited tumor growth (range: 40-73%), and GemCis caused a greater reduction (range: 80-86%) than NPT (57-76%). Again, an additive effect was observed with the combination of TE and chemotherapy. In all CDX and PDX subcutaneous tumors, reduction in tumor cell proliferation, measured by Ki67 staining, corresponded with tumor growth inhibition data. Further, decreased levels of serotonin were observed by TE treatment in all CDX and PDX tumors. Conclusion: In several CCA preclinical models, TE exhibited marked antitumor efficacy and it enhanced GemCis or NPT chemotherapy response. Hence, combination therapies with TE have the potential to improve clinical CCA therapy. Citation Format: Lily Darman, Margaret A. Schwarz, Roderich Schwarz, Niranjan Awasthi. Enhancing chemotherapy response by telotristat ethyl, an inhibitor of tryptophan hydroxylase involved in serotonin synthesis, in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 480.

Telotristat Etiprate alleviates rheumatoid arthritis by targeting LGALS3 and affecting MAPK signaling.

Rheumatoid arthritis (RA) is one of the most widespread chronic immune-mediated inflammatory diseases characterized by continuous erosion of bone and cartilage by synovial hyperplasia. Telotristat Etiprate is an inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the biosynthesis of serotonin. Telotristat Etiprate can be used in the treatment of carcinoid syndrome. The purpose of this study was to explore the effect of Telotristat Etiprate on RA and its mechanism. We investigated Telotristat Etiprate in collagen-induced arthritis (CIA) model mice and in rheumatoid arthritis synovial fibroblasts (RASFs). Results showed that Telotristat Etiprate had anti-inflammatory effects both in vitro and in vivo, can inhibit the invasion and migration of cells, inhibit the formation of pannus, and induce cell apoptosis. Transcriptome sequencing (RNA-seq) and mass spectrometry analysis showed that Galectins-3 (LGALS3) could be a newly identified target of Telotristat Etiprate, affecting the phosphorylation of the MAPK signaling pathway through UBE2L6, thereby improving RA.

Reserpine and PCPA reduce heat tolerance in Drosophila melanogaster

Drosophila melanogaster is a model organism to study molecular mechanisms and the role of the genes and proteins involved in thermal nociception. Monoamines (i.e. dopamine) have been involved in temperature preference behavior in D. melanogaster. Therefore, we investigated whether the monoamines, particularly dopamine and serotonin, participate in the response to thermal nociceptive stimuli in D. melanogaster. Flies were treated with reserpine (an inhibitor of vesicular monoamines transporter, 3–300 μM), 3-Iodo-L-tyrosine (3-I-T, an inhibitor of tyrosine hydroxylase, 16.28–65.13 mM), and para-Chloro-DL-phenylalanine (PCPA, an inhibitor of tryptophan hydroxylase, 20–80 mM); then, the flies were subjected to tests of thermal tolerance and avoidance of noxious heat. Climbing behavior was used as a test to evaluate locomotor activity. Reserpine reduces the thermal tolerance profile of the D. melanogaster, as well as the avoidance of noxious heat and locomotor activity depending on the concentration. PCPA, but not 3-I-T, decreased heat tolerance and avoidance of noxious heat. These data suggest that monoamines, particularly serotonin, are associated with the impaired avoidance of noxious heat which could be related to the reduction of heat tolerance in D. melanogaster.

Involvement of the serotonergic system in the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine in mice

Depression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results. To evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300mg/kg). MeSeI administered 30min before the FST and the TST reduced immobility time at doses from 1mg/kg and at 50mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100mg/kg, intraperitoneally-i.p. for 4days), with ketanserin, a 5-HT2A/2C receptor antagonist (1mg/kg, i.p.), and with GR113808, a 5-HT4 receptor antagonist (0.1mg/kg, i.p.), but not with WAY100635, a selective 5-HT1A receptor antagonist (0.1mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT3 receptor antagonist (1mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT2A, 5 -HT2C, and 5-HT4 receptors by molecular docking. MeSeI (300mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice. In summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression.

Treatment of Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS), which mainly occurs in children and young adults. Treatment options with proven clinical efficacy for PPNAD include adrenalectomy (bilateral or unilateral adrenalectomy) and drug treatment to control hypercortisolemia. Previously, the main treatment of PPNAD is bilateral adrenal resection and long-term hormone replacement after surgery. In recent years, cases reports suggest that unilateral or subtotal adrenal resection can also lead to long-term remission in some patients without the need for long-term hormone replacement therapy. Medications for hypercortisolemia, such as Ketoconazole, Metyrapone and Mitotane et.al, have been reported as a preoperative transition for in some patients with severe hypercortisolism. In addition, tryptophan hydroxylase inhibitor, COX2 inhibitor Celecoxib, somatostatin and other drugs targeting the possible pathogenic mechanisms of the disease are under study, which are expected to be applied to the clinical treatment of PPNAD in the future. In this review, we summarize the recent progress on treatment of PPNAD, in which options of surgical methods, research results of drugs acting on possible pathogenic mechanisms, and the management during gestation are described in order to provide new ideas for clinical treatment.

Real-World Clinical and Patient-Reported Outcomes from the Longitudinal Telotristat Ethyl Treatment Registry of Patients with Neuroendocrine Tumors.

BackgroundTelotristat ethyl (TE) is an oral tryptophan hydroxylase inhibitor approved for the treatment of carcinoid syndrome diarrhea (CSD) in combination with somatostatin analogs (SSAs).MethodsThis prospective, observational, single-arm study evaluated long-term patient-reported outcomes for adults initiating TE in US clinical practice from 2017 through January 2022. The primary objective was satisfaction with overall CS symptom control 6 months after initiating TE. Secondary objectives evaluated satisfaction with control of CSD, flushing, and CS symptoms, as well as work productivity/activity impairment, SSA use, and weight. All analyses were descriptive in nature.ResultsA total of 223 patients completed the baseline survey; 56% also completed the 6-month follow-up survey. Mean age was 61 years and 61% were women. After 6 months of TE treatment, the majority of patients (76%, n=95/125) reported being satisfied with control of their CS symptoms which was markedly improved from baseline (41%, n=91). Similarly, the majority of patients (78%, n=97/125) were satisfied with control of their CSD after 6 months of TE, markedly improved from baseline (36%).ConclusionThis longitudinal observational study showed improvements in real-world clinical and humanistic outcomes for patients with CS and at least 6 months of TE treatment.

Structure-Based Design of Xanthine-Benzimidazole Derivatives as Novel and Potent Tryptophan Hydroxylase Inhibitors.

Tryptophan hydroxylases catalyze the first and rate-limiting step in the synthesis of serotonin. Serotonin is a key neurotransmitter in the central nervous system and, in the periphery, functions as a local hormone with multiple physiological functions. Studies in genetically altered mouse models have shown that dysregulation of peripheral serotonin levels leads to metabolic, inflammatory, and fibrotic diseases. Overproduction of serotonin by tumor cells causes severe symptoms typical for the carcinoid syndrome, and tryptophan hydroxylase inhibitors are already in clinical use for patients suffering from this disease. Here, we describe a novel class of potent tryptophan hydroxylase inhibitors, characterized by spanning all active binding sites important for catalysis, specifically those of the cosubstrate pterin, the substrate tryptophan as well as directly chelating the catalytic iron ion. The inhibitors were designed to efficiently reduce serotonin in the periphery while not passing the blood-brain barrier, thus preserving serotonin levels in the brain.

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome

This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.

Monoaminergic system involvement in the antidepressant-like and anxiolytic-like properties of novel β-dihydroagarofuran sesquiterpene alkaloid and triterpenes isolated from Gymnosporia heterophylla aerial parts in mice

Gymnosporia heterophylla (synonym Maytenus) is widely used in folk medicine for the treatment of various illness including neurological diseases. This study presents the antidepressant-like and anxiolytic-like effects of novel bioactive constituents; 3,4˗seco-1-hydroxy-21-oxoolean-3,11-olide (A2), 1β,2β-diacetoxy-9β-benzoyloxy-6α-nicotinoyloxy-β-dihydroagarofuran (A5) as well as known 3-acetoxy-1β-hydroxyLupe-20(29)-ene (selective COX-2; A4) from the aerial parts of G. heterophylla. The antidepressant-like effect was studied using the forced swim test (FST) while the elevated plus maze test (EPMT) and open field test (OFT) were employed for anxiolytic-like effect. Acute treatment with A4 and A5 (0.5, 5 or 10 mg/kg) significantly reduced the duration of immobility and immobile episodes with prolongation of immobility latency in the FST with peak effects observed at 10 and 0.5 mg/kg, respectively. Moreover, antidepressant-like effect of A4 and A5 were relatively better than that of fluoxetine. Conversely, the pretreatment of mice with prazosin (1 mg/kg, α1-adrenoceptor antagonist), yohimbine (1 mg/kg; α2-adrenoceptor antagonist), or sulpiride (50 mg/kg; dopamine D2-receptor antagonist) reversed antidepressant-like effect of A4 and A5 but not WAY 100635 (10 mg/kg, i.p., selective 5-HT1A receptor antagonist), GR 127935 (5 mg/kg, i.p., selective 5-HT1B receptor antagonist), metergoline (4 mg/kg, i.p, non-selective 5-HT2 receptor antagonist), ketanserin (5 mg/kg, i.p., a selective 5-HT2A receptor antagonist) or p-chlorophenylalanine (pCPA) (100 mg/kg, i.p., tryptophan hydroxylase inhibitor) in the FST. Interestingly, A2, A4 and A5 significantly increased the time spent in the open arms of the EPM suggestive of anxiolytic-like action. Findings from this study showed that the novel β-dihydroagarofuran sesquiterpene alkaloid and triterpenes possesses antidepressant-like and anxiolytic-like effects through enhancement of monoaminergic signaling.

Intracerebroventricular injection of taurine induces hypothermia through modifying monoaminergic pathways in chicks

Brain monoamines are reported to regulate body temperature and food intake. The objective of this study was to investigate the mechanism of brain monoamine metabolism in taurine-induced hypothermia and appetite suppression. In Experiment 1, 5-day-old male Julia layer chicks (n = 10) were subjected to intracerebroventricular (ICV) injection with saline or taurine (5 μmol/10 μL). In Experiment 2, the chicks were ICV injected with saline, taurine, fusaric acid (dopamine-β-hydroxylase inhibitor: 558 nmol), or taurine with fusaric acid. In Experiment 3, the chicks were ICV injected with saline, taurine, para-chlorophenylalanine (PCPA, tryptophan hydroxylase inhibitor: 400 nmol), or taurine with PCPA. In Experiment 4, the chicks were ICV injected with saline, taurine, clorgyline (monoamine oxidase inhibitor: 81 nmol), or taurine with clorgyline. Central taurine lowered rectal temperature at 30 min post-injection and increased norepinephrine in the brainstem and its metabolite 3-methoxy-4-hydroxyphenylglycol in both the diencephalon and brainstem. Similarly, taurine treatment induced increases in serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid in the diencephalon. Fusaric acid completely and PCPA partially, but not clorgyline, attenuated taurine-induced hypothermia. The anorexigenic effect of taurine was partially attenuated by PCPA, but not fusaric acid nor clorgyline. In conclusion, central taurine activates dopamine-β-hydroxylase and tryptophan hydroxylase to produce norepinephrine and 5-HT, and then induces hypothermia, but 5-HT alone may be linked with taurine-induced anorexia in chicks.

Telotristat ethyl with PRRT in the treatment of well differentiated neuroendocrine tumors.

e16205 Background: Feasibility of telotristat ethyl, a tryptophan hydroxylase inhibitor in serotonin synthesis, in combination with PRRT/lutetium Lu 177 DOTATATE is unclear in well differentiated neuroendocrine tumors (WDNET). We explore real world treatment patterns in patients receiving telotristat and PRRT. Methods: A retrospective study was conducted on 67 patients with a histopathologic diagnosis of WDNET, treated with telotristat and/or PRRT at the Winship Cancer Institute in Emory University from 2018 to 2022. OS and PFS were assessed by Kaplan Meier curves. Descriptive analysis was performed with associations characterized by multi- (MVA) and univariate (UVA) Cox proportional hazards model, t-test, and ANOVA. Results: Of the 67 patients, 44 received PRRT alone and 23 received PRRT with telotristat for carcinoid symptoms. Median age was 69 (range 18-80) with male 57% and white race 65%. 16 (26%), 41 (67%), 4 (7%) had grades 1 (Ki67 &lt; 3%), 2 (3-20%), and 3 (&gt; 20%) disease respectively. The plurality (n = 31, 46%) had primary small bowel (SB) NETs and 40 (65%) underwent primary NET resection. 2 had gastrinomas, 1 VIPoma, and 1 insulinoma. All had liver and 23 (40%) had bone metastases. Most patients received PRRT as 3rd line therapy. 59 (88%) in the entire cohort and 17 (74%) in the telotristat group received 4 doses of PRRT. 15 (17%) in the entire cohort had delayed/dose reduced PRRT. Telotristat was associated with improved diarrhea and decreased serotonin (all p &lt; 0.003). 16 (70%) on telotristat reported improvement in diarrhea and flushing. 5 (17%) had grade 3/4 adverse events while receiving telotristat. Of those, 1 developed hypotension, 1 hypokalemia, 1 myelodysplastic syndrome, 1 febrile neutropenia, and 1 anemia and pursued hospice care after a cerebrovascular event. Median(m) OS, PFS, and follow up were 216, 33, 67 months (mo) for the entire cohort respectively. 6 (26%) died in the telotristat/PRRT group vs 17 (39%) PRRT only. 10 (43%) in the telotristat group progressed vs 18 (41%) in PRRT only. mPFS was 33 mo in telotristat/PRRT and not reached (NR) in PRRT only (p = 0.684). mOS was NR in the telotristat/PRRT group vs 216 mo in PRRT only (p = 0.717). In MVA, OS was associated with primary NET resection (HR 0.232), age &gt; 60 (HR 7.88), SB primary NET (HR 0.097), and PRRT completion (HR 0.062, all p &lt; 0.05). In MVA, PFS was associated with diarrhea (HR 3.7) and small bowel primary NET (HR 0.264, all p &lt; 0.05). In UVA, lower OS and PFS were associated with elevated chromogranin A (CGA) (upper limit 225, HR 3.34, p &lt; 0.02). Initial neutrophil-eosinophil ratio (NER) was associated with OS (HR 21.2) and PFS (HR 10.8) in MVA with optimal cutoff of 35.28 ( both p &lt; 0.02). Conclusions: Patients with primary SB WDNETs and carcinoid symptoms benefited from receiving telotristat/PRRT in our study. CGA, serotonin, and NER are potential biomarkers to assess disease patterns. Multi-institutional studies and further follow up are needed to confirm these findings.

Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease.

Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.

Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice.

Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25µg/kg, p.o.) for 7days, similar to fluoxetine (10mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA - 100mg/kg, i.p., for 4days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.