-
BMC Endocrine Disorders Jun 2024An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary...
PURPOSE
An increase of IGF-1 has been reported during therapy with dopamine agonists (DA) for prolactinomas; in such cases a correct diagnosis is pivotal to avoid an unnecessary reduction or withdrawal of DA, which are needed to maintain normal prolactin levels. This study was aimed to measure IGF-1 levels, at baseline and during follow-up, in a cohort of patients with prolactinoma, treated with cabergoline, stratified by body mass index.
METHODS
We retrospectively enrolled 35 patients (15 F/20 M; age m ± SD, years: 43.4 ± 13.7) with prolactinoma (21 microadenomas and 14 macroadenomas) who were followed-up at the Endocrinology Unit, in Siena, and with available pituitary hormone assessment at baseline and during follow-up (m ± SD, years: 2.74 ± 0.55).
RESULTS
IGF-1 increased in the whole cohort, but remaining within normal range, except two patients, in whom acromegaly was ruled out with oral glucose tolerance test. After dividing patients by weight, this trend was confirmed only in subjects with overweight and obesity (OV/OB) (p = 0.04). Interestingly, the reduction of prolactin levels was significantly greater in the OV/OB compared to normal-weight patients (median decrease of 97.5% versus 88.2%, p = 0.04).
CONCLUSIONS
Since DA and normalization of prolactin are known to improve insulin sensitivity, we speculated they have favored the increase of IGF-1 in OV/OB. Our results should be confirmed and the hypothesis proven by further studies.
Topics: Humans; Prolactinoma; Insulin-Like Growth Factor I; Female; Male; Adult; Retrospective Studies; Dopamine Agonists; Pituitary Neoplasms; Middle Aged; Cabergoline; Body Weight; Follow-Up Studies; Prolactin; Body Mass Index; Prognosis
PubMed: 38902646
DOI: 10.1186/s12902-024-01622-4 -
International Journal of Molecular... May 2024Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations... (Review)
Review
Until the late 1800s, drug development was a chance finding based on observations and repeated trials and errors. Today, drug development must go through many iterations and tests to ensure it is safe, potent, and effective. This process is a long and costly endeavor, with many pitfalls and hurdles. The aim of the present review article is to explore what is needed for a molecule to move from the researcher bench to the patients' bedside, presented from an industry perspective through the development program of cariprazine. Cariprazine is a relatively novel antipsychotic medication, approved for the treatment of schizophrenia, bipolar mania, bipolar depression, and major depression as an add-on. It is a D3-preferring D3-D2 partial agonist with the highest binding to the D3 receptors compared to all other antipsychotics. Based on the example of cariprazine, there are several key factors that are needed for a molecule to move from the researcher bench to the patients' bedside, such as targeting an unmet medical need, having a novel mechanism of action, and a smart implementation of development plans.
Topics: Humans; Antipsychotic Agents; Piperazines; Receptors, Dopamine D3; Schizophrenia; Animals; Bipolar Disorder; Drug Development
PubMed: 38891871
DOI: 10.3390/ijms25115682 -
JCI Insight Jun 2024Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause autosomal recessive intellectual disability and...
Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (trappc9) cause autosomal recessive intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links trappc9 to non-alcoholic fatty liver disease (NAFLD). Trappc9-deficient mice have been shown to appear overweight shortly after weaning. Here, we analyzed serum biochemistry and histology of adipose and liver tissues to determine the incidence of obesity and NAFLD in trappc9-deficient mice and combined transcriptomic and proteomic analyses, pharmacological studies, and biochemical and histological examinations of postmortem mouse brains to unveil mechanisms involved. We found that trappc9-deficient mice presented with systemic glucose homeostatic disturbance, obesity and NAFLD, which were relieved upon chronic treatment combining dopamine receptor D2 (DRD2) agonist quinpirole and DRD1 antagonist SCH23390. Blood glucose homeostasis in trappc9-deficient mice was restored upon administrating quinpirole alone. RNA-sequencing analysis of DRD2-containing neurons and proteomic study of brain synaptosomes revealed signs of impaired neurotransmitter secretion in trappc9-deficient mice. Biochemical and histological studies of mouse brains showed that trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that trappc9 loss-of-function causes obesity and NAFLD by constraining dopamine synapse formation.
PubMed: 38889014
DOI: 10.1172/jci.insight.181339 -
Neuropharmacology Jun 2024Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for...
Kappa opioid receptors (KORs) are implicated in the pathophysiology of various psychiatric and neurological disorders creating interest in targeting the KOR system for therapeutic purposes. Accordingly, navacaprant (NMRA-140) is a potent, selective KOR antagonist being evaluated as a treatment for major depressive disorder. In the present report, we have extended the pharmacological characterization of navacaprant by further demonstrating its selective KOR antagonist properties and confirming its lack of agonist activity at KORs and related targets involved in opioid-related abuse. Using CHO-K1 cells expressing human KOR, mu (MOR), or delta (DOR) opioid receptors, navacaprant demonstrated selective antagonist properties at KOR (IC = 0.029 μM) versus MOR (IC = 3.3 μM) and DOR (IC > 10 μM) in vitro. In vivo, navacaprant (10-30 mg/kg, i.p.) dose-dependently abolished KOR-agonist induced analgesia in the mouse tail-flick assay. Additionally, navacaprant (10, 30 mg/kg, p.o.) significantly reduced KOR agonist-stimulated prolactin release in mice and rats, confirming KOR antagonism in vivo. Navacaprant showed no agonist activity at any opioid receptor subtype (EC > 10 μM) in vitro and exhibited no analgesic effect in the tail-flick assays at doses ≤100 mg/kg, p.o. thereby confirming a lack of opioid receptor agonist activity in vivo. Importantly, navacaprant did not alter extracellular dopamine concentrations in the nucleus accumbens shell of freely-moving rats following doses ≤100 mg/kg, p.o., whereas morphine (10, 20 mg/kg, i.p.) significantly increased dopamine levels. These results demonstrate that navacaprant is a KOR-selective antagonist with no pharmacological properties implicated in opioid-related abuse.
PubMed: 38876309
DOI: 10.1016/j.neuropharm.2024.110037 -
PCN Reports : Psychiatry and Clinical... Dec 2023The domain of psychiatric drug development is currently witnessing a notable transformation, with a paramount emphasis on targeting nonmonoamine receptors and exploring... (Review)
Review
The domain of psychiatric drug development is currently witnessing a notable transformation, with a paramount emphasis on targeting nonmonoamine receptors and exploring inventive mechanisms of action. This paper presents an overview of the ongoing advancements in antipsychotic and antidepressant drug development. Historically, antipsychotics predominantly targeted dopamine receptors, but there is now an escalating interest in drugs that act on alternative receptors, exemplified by the TAAR1 receptor. One noteworthy candidate is Ulotaront (SEP-363856), an agent acting as a TAAR1 agonist with 5-HT1A agonist activity, demonstrating promising outcomes in the treatment of schizophrenia, devoid of extrapyramidal symptoms or metabolic side-effects. Similarly, MIN-101 (Roluperidone) and KarXT are currently in development, with its focus on addressing the symptoms in schizophrenia. In the domain of antidepressants, novel therapeutic approaches have surfaced, such as Auvelity, a Food and Drug Administration (FDA)-approved NMDA receptor antagonist synergistically combined with Bupropion to enhance its effects. Another notable candidate is Zuranolone, operating as a GABA A receptor-positive allosteric modulator, showcasing efficacy in treating major depressive disorder (MDD) and postpartum depression. Additionally, TAK-653 (NBI-1065845) and MJI821 (Onfasprodil) have emerged as potential antidepressants targeting AMPA receptors and NMDA receptor 2B (NR2B) negative allosteric modulation, respectively. This paper underscores the transformative potential of these novel drug candidates in psychiatric treatment and their ability to address cases that were previously treatment-resistant. By focusing on nonmonoamine receptors and introducing innovative mechanisms, these drugs offer a promising prospect of improved outcomes for individuals suffering from schizophrenia and MDD. Thus, sustained attention and dedication to the development of such drugs are essential to augmenting the therapeutic options available for psychiatric patients.
PubMed: 38868733
DOI: 10.1002/pcn5.157 -
Journal of the ASEAN Federation of... 2024There has been an increasing awareness of the effects of combining bromocriptine-QR with other medications for diabetes mellitus type 2. This study aimed to assess the... (Meta-Analysis)
Meta-Analysis Review
Efficacy and Safety of Bromocriptine-QR as an Adjunctive Therapy on Glycemic Control in Subjects with Uncontrolled Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.
INTRODUCTION
There has been an increasing awareness of the effects of combining bromocriptine-QR with other medications for diabetes mellitus type 2. This study aimed to assess the efficacy and safety of bromocriptine-QR as an adjunctive therapy for patients with uncontrolled type 2 diabetes mellitus.
METHODOLOGY
This systematic review is registered at the International Prospective Register of Systematic Reviews (CRD42022360326). Literature search was done via MEDLINE, NCBI, Google Scholar, Science Direct, Europe PMC and Cochrane Library databases. We included randomized controlled trials with participants 18 years old and above with uncontrolled type 2 diabetes mellitus. The primary outcome of interest is the efficacy and safety of bromocriptine-QR as an adjunctive therapy for glycemic control. Case reports, case series, reviews and animal studies were excluded. The risk of bias was reviewed using the Cochrane Risk of Bias tool. Meta-analysis was performed using Review Manager 5.4 and presented as a weighted mean difference and 95% confidence interval for changes from the baseline level.
RESULTS
Nine studies were included in the systematic review with a total of 2709 participants. The baseline HbA1c in the bromocriptine-QR group was 7.42% and 7.51% in the control group. The bromocriptine-QR group was favoured, outperforming the control group in terms of reducing hemoglobin A1c(HbA1c), with a statistically significant difference (weighted mean difference -0.6%; 95% CI [-0.83,-0.36]; p<0.00001). The most common side effects were nausea (33.75% vs 6.92%), fatigue (13.11% vs 5.94%), and headache (11.17% vs 6.87%).
CONCLUSION
Administration of bromocriptine-QR at a dose range of 1.6 to 4.8 mg/day as an adjunctive therapy reduced HbA1c and FBG in patients with uncontrolled type 2 diabetes mellitus (T2DM). However, there were also statistically greater odds of the occurrence of adverse events such as nausea, vomiting, and headache compared to controls.
Topics: Humans; Diabetes Mellitus, Type 2; Bromocriptine; Glycemic Control; Hypoglycemic Agents; Blood Glucose; Glycated Hemoglobin; Treatment Outcome; Drug Therapy, Combination; Dopamine Agonists
PubMed: 38863918
DOI: 10.15605/jafes.039.01.19 -
American Journal of Cancer Research 2024ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary...
Dopamine pre-treatment impairs the anti-cancer effect of integrated stress response- and TRAIL pathway-inducing ONC201, ONC206 and ONC212 imipridones in pancreatic, colorectal cancer but not DMG cells.
ONC201 (originally discovered as TRAIL-Inducing Compound #10 or TIC10) and analogue ONC206 have been found to induce an integrated stress response with suggested primary targets and mechanisms involving targeting mitochondrial protein ClpP and antagonism of dopamine receptors D2/3 (DRD2/3). We hypothesized that dopamine, the agonist of DRD2, may counteract ONC201 or ONC206 for DRD2/3 and impair the anti-cancer effect of ONC201 or ONC206, thus protect the tumor cells from the cytotoxic effect of ONC201 or ONC206. We therefore pre-treated cancer cells from different tissue origins including breast cancer, pancreatic cancer, colorectal cancer, and diffuse midline glioma (DMG) with dopamine, followed by treatment of ONC201, ONC206 or ONC212. We observed that 48 hours of pre-treatment with dopamine impaired the cell viability suppression effect of ONC201, ONC206 and ONC212 in pancreatic cancer cells and colorectal cancer cells. We pre-treated multiple cancer cell lines with dopamine for one week followed by ONC201, ONC206, or ONC212 treatment and performed colony assays. Pre-treatment with dopamine impaired the anti-cancer effect of ONC201 or ONC206 in pancreatic cancer and colorectal cancer. Impairment of ONC212 effect by pre-treatment with dopamine was also seen in colony assay for colorectal cancer, but not in pancreatic cancer cells by colony assay. No protection from killing by imipridones was observed with DRD2 agonist sumanirole in tumor cells, or with brain tumor cell lines pretreated with dopamine. Immunoblotting was conducted to investigate whether dopamine pre-treatment impacts signaling pathways reported to be affected by ONC201. The dopamine pre-treatment did not impact changes in ATF4, CHOP, DR5 and ClpX which were reported to be affected by ONC201. The mechanism of impairment of ONC201/206/212 effect caused by dopamine pre-treatment appears to involve upregulation of anti-apoptotic p-Bad, XIAP, FLIP and pAkt. Our results shed light on mechanisms of cancer cell protection by dopamine after imipridone treatment, heterogeneity among different tumor cell types, and suggest that effects of dopamine adaptation on tumor cells may impact on cell survival pathways in ways that may or may not depend on expression of dopamine receptors.
PubMed: 38859853
DOI: 10.62347/ZOTV8006 -
Neurobiology of Disease Aug 2024Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal...
Parkinson's disease is caused by a selective vulnerability and cell loss of dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson's disease therapy, dopamine loss is counteracted by the administration of L-DOPA, which is initially effective in ameliorating motor symptoms, but over time leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and in recent years, a role has been established for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors may have a role and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson's disease. Administration of RS 67333, a 5-HT4 receptor partial agonist, reduces L-DOPA-induced dyskinesia without altering L-DOPA's pro-kinetic effect. In the dorsolateral striatum, we find 5-HT4 receptor to be predominantly expressed in D2R-containing medium spiny neurons, and its expression is altered by dopamine depletion and L-DOPA treatment. We further show that 5-HT4 receptor agonism not only reduces L-DOPA-induced dyskinesia, but also enhances the activation of the cAMP-PKA pathway in striatopallidal medium spiny neurons. Taken together, our findings suggest that agonism of the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic approach to reduce L-DOPA-induced dyskinesia.
Topics: Animals; Dyskinesia, Drug-Induced; Levodopa; Oxidopamine; Mice; Male; Mice, Inbred C57BL; Serotonin 5-HT4 Receptor Agonists; Antiparkinson Agents; Corpus Striatum; Receptors, Serotonin, 5-HT4; Parkinsonian Disorders; Pyridines; Neurons; Piperidines; Pyrimidines
PubMed: 38852753
DOI: 10.1016/j.nbd.2024.106559 -
Schizophrenia Research Jun 2024PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the...
BACKGROUND
PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia.
METHODS
Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks.
RESULTS
The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight.
CONCLUSIONS
These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted.
TRIAL REGISTRATION
Clinicaltrials.gov identifier: NCT03055338.
PubMed: 38851166
DOI: 10.1016/j.schres.2024.05.019 -
Frontiers in Neurology 2024Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists....
INTRODUCTION
Impulse control disorders (ICDs) are defined as excessive and repetitive behaviors that may affect Parkinson's disease (PD) patients exposed to dopamine agonists. Current data on ICDs in patients with early-onset Parkinson's disease (EOPD) is lacking. In this study we aim to assess the frequency of use of dopamine agonists, the prevalence of ICDs, and to explore potential factors associated with their development in patients with EOPD.
METHODS
We used the Mayo Clinic Data Explorer system to investigate a population-based cohort of EOPD patients between 1990 and 2022 at Mayo Clinic, Rochester, MN. We used ICD coding for parkinsonism; then, we reviewed all the clinical records and included only those patients with a clinical diagnosis of PD with symptoms onset at or before the age of 50, and who developed ICDs after using therapeutic doses of dopamine agonists.
RESULTS
A total of 831 (513 males and 318 females) patients with EOPD were included with a median age at symptom onset of 42 years of age (CI: 37-46). Dopamine agonists were used in 49.7% of all patients; of these, only 14.5% developed symptoms of one or more ICDs. Hypersexuality was the most commonly observed ICD (38.3%), and the only one having a statistically significant male predominance ( = 0.011).
CONCLUSION
ICDs are common in EOPD, particularly when associated with the use of dopamine agonists.
PubMed: 38841693
DOI: 10.3389/fneur.2024.1404904