-
Expert Opinion on Drug Safety 2023Levodopa remains the gold standard for treatment of Parkinson's disease (PD). Patients develop complications with disease progression, necessitating adjunctive therapy... (Review)
Review
INTRODUCTION
Levodopa remains the gold standard for treatment of Parkinson's disease (PD). Patients develop complications with disease progression, necessitating adjunctive therapy to control fluctuations in motor and non-motor symptoms and dyskinesia. Knowledge of medication safety and tolerability is critical to ascertain the benefit-risk ratio and select an adjunctive therapy that provides the highest chance for medication adherence. Posing a challenge are the sheer abundance of options, stemming from the development of several new drugs in recent years, as well as differences in commercial drug availability worldwide.
AREAS COVERED
This review evaluates the efficacy, safety, and tolerability of current US FDA-approved pharmacotherapies for levodopa-treated PD patients, including dopamine agonists, monoamine oxidase type-B inhibitors, catechol-O-methyltransferase inhibitors, the N-methyl-D-aspartate receptor antagonist amantadine, and the adenosine receptor antagonist istradefylline. Data were taken from pivotal phase III randomized controlled and post-surveillance studies, when available, that directly led to FDA-approval.
EXPERT OPINION
No strong evidence exists to support use of a specific adjunctive treatment for improving Off time. Only one medication has demonstrated improvement in dyskinesia in levodopa-treated PD patients; however, every patient cannot tolerate it and therefore adjunctive therapy should be tailored to an individual's symptoms and risk for specific adverse effects.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Catechol O-Methyltransferase; Dyskinesias
PubMed: 37401865
DOI: 10.1080/14740338.2023.2227096 -
Nature Cancer Mar 2024Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor...
Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT-G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.
Topics: Humans; Histone-Lysine N-Methyltransferase; Dopamine Plasma Membrane Transport Proteins; Colonic Neoplasms; Neoplastic Stem Cells; Piperazines
PubMed: 38351181
DOI: 10.1038/s43018-024-00727-y -
Journal of the American Academy of... Sep 2023Antipsychotic-induced hyperprolactinemia is common in children and adolescents, but this quotidian presence in our clinics should neither reassure us nor make us...
Antipsychotic-induced hyperprolactinemia is common in children and adolescents, but this quotidian presence in our clinics should neither reassure us nor make us complacent. The report by Koch and colleagues stands out against the landscape of trials describing the adverse effects of psychotropic medications in youth. It goes beyond the typical examination of adverse effects in most clinical trials. The authors followed children and adolescents aged 4 to 17 years who were dopamine-serotonin receptor antagonist naive (≤1-week exposure) or free, and serially evaluated not only serum prolactin concentrations but medication concentrations and side effects for 12 weeks after participants began aripiprazole, olanzapine, quetiapine, or risperidone. This report provides insights into the temporal course of adverse effects, examines differential tolerability among dopamine-serotonin receptor antagonists, links specific adverse effects-galactorrhea, decreased libido, and erectile dysfunction-with prolactin concentrations in youth, and focuses on the clinical aspects of hyperprolactinemia and related adverse effects in children and adolescents.
Topics: Male; Female; Adolescent; Child; Humans; Antipsychotic Agents; Hyperprolactinemia; Prolactin; Dopamine; Risperidone; Aripiprazole
PubMed: 37172820
DOI: 10.1016/j.jaac.2023.05.003 -
Cancer Biology & Therapy Dec 2023Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an...
Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for cancer patients with homologous recombination (HR) deficient tumors. The imipridone ONC206 is an orally bioavailable dopamine receptor D2 antagonist and mitochondrial protease ClpP agonist that has anti-tumorigenic effects in endometrial cancer via induction of apoptosis, activation of the integrated stress response and modulation of PI3K/AKT signaling. Both PARP inhibitors and imipridones are being evaluated in endometrial cancer clinical trials but have yet to be explored in combination. In this manuscript, we evaluated the effects of the PARP inhibitor olaparib in combination with ONC206 in human endometrioid endometrial cancer cell lines and in a genetically engineered mouse model of endometrial cancer. Our results showed that simultaneous exposure of endometrial cancer cells to olaparib and ONC206 resulted in synergistic anti-proliferative effects and increased cellular stress and apoptosis in both cell lines, compared to either drug alone. The combination treatment also decreased expression of the anti-apoptotic protein Bcl-2 and reduced phosphorylation of AKT and S6, with greater effects compared to either drug alone. In the transgenic model of endometrial cancer, the combination of olaparib and ONC206 resulted in a more significant reduction in tumor weight in obese and lean mice compared to ONC206 alone or olaparib alone, together with a considerably decreased Ki-67 and enhanced H2AX expression in obese and lean mice. These results suggest that this novel dual therapy may be worthy of further exploration in clinical trials.
Topics: Female; Humans; Mice; Animals; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Cell Proliferation; Cell Line, Tumor; Antineoplastic Agents; Endometrial Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Phthalazines; Receptors, Dopamine
PubMed: 37069726
DOI: 10.1080/15384047.2023.2202104 -
Journal of Medicinal Chemistry Sep 2023Pharmacological targeting of the dopamine D receptor (DR)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for...
Pharmacological targeting of the dopamine D receptor (DR)─expressed in brain regions that control cognition, attention, and decision-making─could be useful for several neuropsychiatric disorders including substance use disorders (SUDs). This study focused on the synthesis and evaluation of a novel series of benzothiazole analogues designed to target DR. We identified several compounds with high DR binding affinity ( ≤ 6.9 nM) and >91-fold selectivity over other D-like receptors (DR, DR) with diverse partial agonist and antagonist profiles. Novel analogue is a potent low-efficacy DR partial agonist, metabolically stable in rat and human liver microsomes, and has excellent brain penetration in rats (AUC > 3). (5-30 mg/kg, i.p.) dose-dependently decreased iv cocaine self-administration in rats, consistent with previous results produced by DR-selective antagonists. Off-target antagonism of 5-HT or 5-HT may also contribute to these effects. Results with support further efforts to target DR in SUD treatment.
Topics: Humans; Animals; Rats; Serotonin; Benzothiazoles; Substance-Related Disorders; Brain; Cocaine
PubMed: 37646374
DOI: 10.1021/acs.jmedchem.3c00734 -
Physiology (Bethesda, Md.) Jan 2024The review deals with the release of endothelium-derived dopamine and 6-nitrodopamine (6-ND) and its effects on isolated vascular tissues and isolated hearts. Basal... (Review)
Review
The review deals with the release of endothelium-derived dopamine and 6-nitrodopamine (6-ND) and its effects on isolated vascular tissues and isolated hearts. Basal release of both dopamine and 6-ND is present in human isolated umbilical cord vessels, human popliteal vessels, nonhuman primate vessels, and reptilia aortas. The 6-ND basal release was significantly reduced when the tissues were treated with -nitro-l-arginine methyl ester and virtually abolished when the endothelium was mechanically removed. 6-Nitrodopamine is a potent vasodilator, and the mechanism of action responsible for this effect is the antagonism of dopamine D-like receptors. As a vasodilator, 6-ND constitutes a novel mechanism by which nitric oxide modulates vascular tone. The basal release of 6-ND was substantially decreased in endothelial nitric oxide synthase knockout (eNOS) mice and not altered in neuronal nitric oxide synthase knockout (nNOS) mice, indicating a nonneurogenic source for 6-ND in the heart. Indeed, in rat isolated right atrium, the release of 6-ND was not affected when the atria were treated with tetrodotoxin. In the rat isolated right atrium, 6-ND is the most potent endogenous positive chronotropic agent, and in Langendorff's heart preparation, it is the most potent endogenous positive inotropic agent. The positive chronotropic and inotropic effects of 6-ND are antagonized by β-adrenoceptor antagonists at concentrations that do not affect the effects induced by noradrenaline, adrenaline, and dopamine, indicating that blockade of the 6-ND receptor is the major modulator of heart chronotropism and inotropism. The review proposes that endothelium-derived catecholamines may constitute a major mechanism for control of vascular tone and heart functions, in contrast to the overrated role attributed to the autonomic nervous system.
Topics: Humans; Rats; Mice; Animals; Dopamine; Nitric Oxide Synthase; Enzyme Inhibitors; NG-Nitroarginine Methyl Ester; Cardiovascular System; Vasodilator Agents; Nitric Oxide; Endothelium
PubMed: 37874898
DOI: 10.1152/physiol.00020.2023 -
Drug Design, Development and Therapy 2023This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of... (Review)
Review
This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D, 5-hydroxytryptamine (5-HT), and 5-HT receptors and a partial agonistic effect on the 5-HT receptor with low affinities for muscarinic M, histamine H, and a adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT and 5-HT receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.
Topics: Humans; Lurasidone Hydrochloride; Schizophrenia; Serotonin; Isoindoles; Thiazoles; Antipsychotic Agents; Weight Gain
PubMed: 37789971
DOI: 10.2147/DDDT.S366769 -
The Journal of Neuroscience : the... Nov 2023Dopamine is a key neurotransmitter in the signaling cascade controlling ocular refractive development, but the exact role and site of action of dopamine D1 receptors...
Dopamine is a key neurotransmitter in the signaling cascade controlling ocular refractive development, but the exact role and site of action of dopamine D1 receptors (D1Rs) involved in myopia remains unclear. Here, we determine whether retinal D1Rs exclusively mediate the effects of endogenous dopamine and systemically delivered D1R agonist or antagonist in the mouse form deprivation myopia (FDM) model. Male C57BL/6 mice subjected to unilateral FDM or unobstructed vision were divided into the following four groups: one noninjected and three groups that received intraperitoneal injections of a vehicle, D1R agonist SKF38393 (18 and 59 nmol/g), or D1R antagonist SCH39166 (0.1 and 1 nmol/g). The effects of these drugs on FDM were further assessed in -knock-out (-KO), retina-specific conditional -KO (-CKO) mice, and corresponding wild-type littermates. In the visually unobstructed group, neither SKF38393 nor SCH39166 affected normal refractive development, whereas myopia development was attenuated by SKF38393 and enhanced by SCH39166 injections. In -KO or -CKO mice, however, these drugs had no effect on FDM development, suggesting that activation of retinal D1Rs is pertinent to myopia suppression by the D1R agonist. Interestingly, the development of myopia was unchanged by either -KO or -CKO, and neither SKF38393 nor SCH39166 injections, nor -KO, affected the retinal or vitreal dopamine and the dopamine metabolite DOPAC levels. Effects on axial length were less marked than effects on refraction. Therefore, activation of D1Rs, specifically retinal D1Rs, inhibits myopia development in mice. These results also suggest that multiple dopamine D1R mechanisms play roles in emmetropization and myopia development. While dopamine is recognized as a "stop" signal that inhibits myopia development (myopization), the location of the dopamine D1 receptors (D1Rs) that mediate this action remains to be addressed. Answers to this key question are critical for understanding how dopaminergic systems regulate ocular growth and refraction. We report here the results of our study showing that D1Rs are essential for controlling ocular growth and myopia development in mice, and for identifying the retina as the site of action for dopaminergic control via D1Rs. These findings highlight the importance of intrinsic retinal dopaminergic mechanisms for the regulation of ocular growth and suggest specific avenues for exploring the retinal mechanisms involved in the dopaminergic control of emmetropization and myopization.
Topics: Male; Mice; Animals; Dopamine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Mice, Inbred C57BL; Myopia; Retina; Receptors, Dopamine D1
PubMed: 37751999
DOI: 10.1523/JNEUROSCI.1196-23.2023 -
Molecular Psychiatry Oct 2023Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ-tetrahydrocannabinol (Δ-THC) is a PPARγ agonist...
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors that regulate gene expression. Δ-tetrahydrocannabinol (Δ-THC) is a PPARγ agonist and some endocannabinoids are natural activators of PPARα and PPARγ. However, little is known regarding their cellular distributions in the brain and functional roles in cannabinoid action. Here, we first used RNAscope in situ hybridization and immunohistochemistry assays to examine the cellular distributions of PPARα and PPARγ expression in the mouse brain. We found that PPARα and PPARγ are expressed in ~70% of midbrain dopamine (DA) neurons. In the amygdala, PPARα is expressed in ~60% of glutamatergic neurons, while PPARγ is expressed in ~60% of GABA neurons. However, no PPARα/γ signal was detected in GABA neurons in the nucleus accumbens. We then used a series of behavioral assays to determine the functional roles of PPARα/γ in the CNS effects of Δ-THC. We found that optogenetic stimulation of midbrain DA neurons was rewarding as assessed by optical intracranial self-stimulation (oICSS) in DAT-cre mice. Δ-THC and a PPARγ (but not PPARα) agonist dose-dependently inhibited oICSS. Pretreatment with PPARα or PPARγ antagonists attenuated the Δ-THC-induced reduction in oICSS and Δ-THC-induced anxiogenic effects. In addition, a PPARγ agonist increased, while PPARα or PPARγ antagonists decreased open-field locomotion. Pretreatment with PPARα or PPARγ antagonists potentiated Δ-THC-induced hypoactivity and catalepsy but failed to alter Δ-THC-induced analgesia, hypothermia and immobility. These findings provide the first anatomical and functional evidence supporting an important role of PPARα/γ in DA-dependent behavior and cannabinoid action.
Topics: Mice; Animals; PPAR alpha; Dopamine; Cannabinoids; PPAR gamma; Dronabinol; Dopaminergic Neurons; Mesencephalon
PubMed: 37479780
DOI: 10.1038/s41380-023-02182-0 -
Journal of Clinical Medicine Sep 2023Uterine Adenomyosis is a benign condition characterized by the presence of endometrium-like epithelial and stromal tissue in the myometrium. Several medical treatments... (Review)
Review
Uterine Adenomyosis is a benign condition characterized by the presence of endometrium-like epithelial and stromal tissue in the myometrium. Several medical treatments have been proposed, but still, no guidelines directing the management of adenomyosis are available. While a hysterectomy is typically regarded as the definitive treatment for adenomyosis, the scarcity of high-quality data leaves patients desiring fertility with limited conservative options. Based on the available data, the levonorgestrel-IUD appears to offer the most favorable outcomes. Other treatments, including GnRH antagonists, dienogest, prolactin, and oxytocin modulators, show promise; however, further data are required to establish their efficacy definitively. Furthermore, there are many emerging therapies that have been developed that seem worthy of consideration in the near future. The aim of this narrative review was to explore the current medical treatments available for adenomyosis and to provide a glimpse of future therapies under assessment. For this scope, we performed a literature search on PubMed and Medline from incept to September 2022 using the keywords: "medical treatment", "non-steroidal anti-inflammatory", "progesterone intrauterine device", "dienogest", "combined oral contraceptives", "gonadotropin releasing hormone agonist", "gonadotropin releasing hormone antagonist", "danazol", "aromatase inhibitors", "ulipristal acetate", "anti-platelet therapy", "dopamine", "oxytocin antagonists", "STAT3", "KRAS", "MAPK", "micro-RNA", "mifepristone", "valproic acid", "levo-tetrahydropalamatine", and "andrographolide". The search was limited to articles in English, with subsequent screening of abstracts. Abstracts were screened to select relevant studies.
PubMed: 37834773
DOI: 10.3390/jcm12196130