Malignant cardiac neoplasms and associated malignancies over 16 years in the USA.

BACKGROUND: Malignant cardiac neoplasms (MCNs), both primary and metastatic, are rare with few epidemiologic studies. METHODS: This retrospective study used the Healthcare Utilization Project/Nationwide Inpatient Sample database from 2002 to 2018 to evaluate the co-occurrences with other malignancies, and mortality of MCNs in the USA. RESULTS: The data contained 7207 weighted discharges of MCN. Median patient age was 51.4 years, 52.29 % were male, in-hospital mortality was 10.51 %, mean cost of hospitalization was $34,280 USD. Lung, mediastinum, and airways were the most common primary cancers associated with metastatic MCN. CONCLUSIONS: MCN are rare in the USA, however they carry a high in-hospital mortality, high morbidity, and hospital cost.

Benign Cardiac Neoplasms in the United States: A Thirteen-Year Review.

Cardiac neoplasms are uncommon tumors. For epidemiological purposes, they can be divided into benign and malignant subtypes, with the former occurring at a significantly higher rate than the latter. Due to their uncommon nature, there are few data-driven studies examining the characteristics and trends of benign cardiac neoplasms. Our retrospective HCUP-NIS data review purports to illuminate some of the trends surrounding benign cardiac neoplasms and their associated co-occurrences. The data consisted of 482,872,274 weighted discharges. There were 45,568 weighted discharges that included a benign cardiac neoplasm. Benign cardiac neoplasms were more often observed in women (64.33%), and the average age was 63.8 years. The most common cardiovascular co-occurrences in patients with benign cardiac neoplasm were atrial tachyarrhythmias (28.93%), heart failure (19.61%), and embolic events such as stroke, myocardial infarct, or pulmonary embolism (19.82%). Other co-occurrences included pulmonary hypertension (7.55%), ventricular arrhythmias (3.23%), and other EKG abnormalities (3.70%). Procedures were numerous in patients with benign cardiac neoplasms. 43% of patients with this diagnosis had some form of cardiac surgery during their hospitalization. Overall, this study found low incidence of benign cardiac neoplasms in the USA during this 13-year study period. However, in the presence of benign cardiac neoplasms, our study showed that cardiovascular co-occurrences are not uncommon and may help to illuminate this otherwise rare diagnosis.

Membrane bound catechol-O-methytransferase is the dominant isoform for dopamine metabolism in PC12 cells and rat brain.

Impaired dopamine activity in the dorsolateral prefrontal cortex (DLPFC) is thought to contribute to cognitive deficits in diseases such as schizophrenia, attention deficit hyperactivity disorder (ADHD) and traumatic brain injury. Catechol-O-methyltransfease (COMT) metabolizes dopamine and is an important regulator of dopamine signaling in the DLPFC. In mammalian species, two isoforms of COMT protein, membrane-bound COMT (MB-COMT) and soluble COMT (S-COMT), are encoded by one COMT gene and expressed widely. While S-COMT is thought to play a dominant role in the peripheral tissues, MB-COMT is suggested to have a greater role in dopamine metabolism in the brain. However, whether a selective inhibitor for MB-COMT may effectively block dopamine metabolism remains unknown. We generated a knockout of MB-COMT in PC12 cells using CRISPR-cas9 technology to evaluate the effect of both MB and S-COMT on dopamine metabolism. Deletion of MB-COMT in PC12 cells significantly decreased homovanillic acid (HVA), completely depleted 3-methyoxytyramine (3-MT), and significantly increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Comparison of the effect of a MB-COMT selective inhibitor LI-1141 on dopamine metabolism in wild type and MB-COMT knockout PC12 cells allowed us to confirm the selectivity of LI-1141 with respect to MB-COMT in cells. Under conditions in which LI-1141 was shown to inhibit only MB-COMT but not S-COMT, it effectively changed dopamine metabolites similar to the effect induced by tolcapone, a non-selective COMT inhibitor, suggesting that selective inhibition of MB-COMT will be effective in blocking dopamine metabolism, providing an attractive therapeutic approach in improving cognition for patients.

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.

RATIONALE: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. OBJECTIVES: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. METHODS: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. RESULTS: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. CONCLUSIONS: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

Synthesis and Evaluation of Bicyclic Hydroxypyridones as Inhibitors of Catechol O-Methyltransferase.

A series of bicyclic pyridones were identified as potent inhibitors of catechol O-methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective IC50s, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.