Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Genetics of Cholesterol-Related Genes in Metabolic Syndrome: A Review of Current Evidence.

Metabolic syndrome (MetS) refers to a cluster of metabolic dysregulations, which include insulin resistance, obesity, atherogenic dyslipidemia and hypertension. The complex pathogenesis of MetS encompasses the interplay between environmental and genetic factors. Environmental factors such as excessive nutrients and sedentary lifestyle are modifiable and could be improved by lifestyle modification. However, genetic susceptibility to MetS, a non-modifiable factor, has attracted the attention of researchers, which could act as the basis for future diagnosis, prognosis, and therapy for MetS. Several cholesterol-related genes associated with each characteristic of MetS have been identified, such as apolipoprotein, lipoprotein lipase (LPL), cholesteryl ester transfer protein (CETP) and adiponectin. This review aims to summarize the genetic information of cholesterol-related genes in MetS, which may potentially serve as biomarkers for early prevention and management of MetS.

Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects.

Abnormality in myocardial copper homeostasis is believed to contribute to the development of cardiomyopathy. Trientine, a copper-chelating drug used in the management of patients with Wilson's disease, demonstrates beneficial effects in patients with hypertrophic cardiomyopathy. This review aims to present the updated development of the roles of trientine in hypertrophic cardiomyopathy. The drug has been demonstrated in animal studies to restore myocardial intracellular copper content. However, its mechanisms for improving the medical condition remain unclear. Thus, comprehending its mechanistic aspects in cardiomyopathy is crucial and could help to expedite future research.

The Potential Use of Ebselen in Treatment-Resistant Depression.

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere's Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium's anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD.

Molecular-Signaling Pathways of Ginsenosides Rb in Myocardial Ischemia-Reperfusion Injury: A Mini Review.

Reperfusion injury following myocardial ischemia remained a challenge for optimal treatment of myocardial infarction. Ginsenosides Rb (G-Rb), the primary components of ginsenoside, have been reported to exert cardioprotective effects via numerous mechanisms. G-Rb1 mediate cardioprotective effects via various signaling pathways, including mitochondrial apoptotic pathway, PI3K/Akt/mTOR, HIF-1α and GRF91, RhoA, p38α MAPK, and eNOS. G-Rb2 activates the SIRT-1 pathway, while G-Rb3 promotes both JNK-mediated NF-κB and PERK/Nrf2/HMOX1. Generally, ginsenosides Rb1, 2, and 3 modulates oxidative stress, inflammation, and apoptosis, contributing to the improvement of structural, functional and biochemical parameters. In conclusion, G-Rb, particularly G-Rb1, have vast potential as a supplement in attenuating reperfusion injury. Translation into a clinical trial is warranted to confirm the beneficial effects of G-Rb.

Reduction in Absolute Neutrophil Counts in Patient on Clozapine Infected with COVID-19.

Despite its severe adverse effects, such as agranulocytosis, clozapine is the primary treatment for treatment-resistant schizophrenia. The established clozapine monitoring system has contributed to reducing agranulocytosis incidence and mortality rates. However, the pandemic coronavirus disease 2019 (COVID-19) has caused changes in the monitoring system. This review aimed to assess the current evidence on the neutrophil changes in the patient on clozapine treatment and infected with COVID-19. Individual cases reported various absolute neutrophil count (ANC) levels, normal, reduced, or elevated. No agranulocytosis case was reported. One case had a borderline moderate-severe ANC level, but the patient was in the 18-week period of clozapine treatment. A cumulative analysis of case the series initially reported inconclusive results. However, a more recent study with a larger sample size reported a significant reduction in the ANC during COVID-19 infection. Nevertheless, this effect is transient as no significant difference was found between the baseline and the post-infection period in ANC levels. In conclusion, COVID-19 is associated with a temporary reduction in ANC levels. The results supported the recommendation to reduce the frequency of clozapine monitoring in the eligible candidates. However, more data are required to confirm the current findings given the limitations, including study design, sample size, and statistical analysis.

Circulating Biomarkers Related to Osteocyte and Calcium Homeostasis Between Postmenopausal Women with and without Osteoporosis.

BACKGROUND: The currently available bone turnover markers are mostly derived from osteoblasts or osteoclasts. Protein markers derived from osteocytes, the most abundant bone cells that can regulate bone turnover activities by other cells, are less explored. OBJECTIVE: This study aimed to compare the circulating markers of osteocytes and calcium homeostasis between Malaysian postmenopausal women with and without osteoporosis. METHODS: Postmenopausal women with (n=20) or without osteoporosis (n=20) as determined by dual- energy X-ray absorptiometry were randomly drawn from a bone health cohort. Their fasting blood was collected and assayed by a multiplex immunoassay panel. RESULTS: The results showed that osteoprotegerin and sclerostin levels were significantly lower among postmenopausal women with osteoporosis than the normal control. No significant differences in other markers were observed between the two groups. Sclerostin level correlated positively with spine Bone Mineral Density (BMD), while 25-hydroxyvitamin D correlated negatively with hip BMD in the control group. No significant correlation was observed between other markers with spine or hip BMD. CONCLUSION: These data provide an insight into the possible roles of osteocyte markers, especially osteoprotegerin and sclerostin, in classifying subjects with osteoporosis. However, the lack of association between these markers and BMD indicates that osteoporosis is a complex and multifactorial condition.

Treatments of Sexual Dysfunction in Opioid Substitution Therapy Patients: A Systematic Review and Meta-Analysis.

Sexual dysfunction is a common condition in the opioid substitution therapy (OST) population. We aimed to determine the efficacy and safety of treatment for sexual dysfunction in the OST population. We searched for interventional studies from Medline, PubMed, and Scopus. Three independent authors conducted a risk-of-bias assessment (RoB 2). A total of seven studies (five randomized-controlled trials, two quasi-experimental), including 473 patients with sexual dysfunction, were identified. Among these, three bupropion (n=207), one trazodone (n=75), two rosa Damascena (n=100), and one ginseng (n=91) studies had reported significantly improve various sexual functioning domains in both genders. In a meta-analysis, bupropion significantly increased male sexual function with standardized mean difference of 0.53; 95% confidence interval of 0.19-0.88; P < 0.01; I2=0. The adverse effects were minor for all agents, and no significant difference between treatment and placebo groups in randomized-controlled trials. These agents have a promising future as therapy for sexual dysfunction in the OST population. However, given the limited sample size and number of studies, further studies should be conducted to confirm the use of these agents.

Factors Associated with Low Bone Density in Opioid Substitution Therapy Patients: A Systematic Review.

Background: Long-term opioid therapy is a risk factor for low bone mineral density (BMD). However, other factors may also contribute to low BMD. Several studies have examined the variables that might contribute to low BMD in patients receiving opioid replacement therapy (OST). However, to our knowledge, there was no systemic review conducted to address this particular issue. Thus, we reviewed the articles on the factors associated with low BMD in the population of opioid use disorder receiving substitution therapy. Methods: The articles that examined correlates or risk factors of low BMD in OST population were retrieved from OVID, SCOPUS, and PUBMED from inception until July 2020 by two independent investigators. Results: A total of 429 articles from three databases were retrieved initially. After screening based on eligibility criteria, five articles were included in the final analysis. The risk factors or correlates found to be significantly associated with low BMD in the OST population include male gender, low body mass index, low testosterone level, methadone or heroin use, and longer duration of heavy alcohol use. The review limitations include small sample sizes and inconsistent definition of variables. Conclusion: OST patients should be screened for BMD and its associated factors. Guidelines and training of practitioners involving in the OST service should be provided to increase the detection of low BMD in the OST population.

UPLC-MS-Based Metabolomics Profiling for α-Glucosidase Inhibiting Property of Parkia speciosa Pods.

Parkia speciosa is a food plant that grows indigenously in Southeast Asia. A great deal of interest has been paid to this plant due to its traditional uses in the treatment of several diseases. The pods contain many beneficial secondary metabolites with potential applications in medicine and cosmetics. However, studies on their phytochemical properties are still lacking. Therefore, the present study was undertaken to profile the bioactive compounds of P. speciosa pods collected from six different regions of Malaysia through ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) and α-glucosidase inhibitory potential. This study applied metabolomics to elucidate the differences between P. speciosa populations found naturally in the different locations and to characterize potential α-glucosidase inhibitors from P. speciosa pods. P. speciosa collected from different regions of Malaysia showed good α-glucosidase inhibitory activity, with a median inhibitory concentration (IC50) of 0.45-0.76 µg/mL. The samples from the northern and northeastern parts of Peninsular Malaysia showed the highest activity. Using UHPLC-QTOF-MS/MS analysis, 25 metabolites were identified in the pods of P. speciosa. The findings unveiled that the pods of P. speciosa collected from different locations exhibit different levels of α-glucosidase inhibitory activity. The pods are a natural source of potent antidiabetic bioactive compounds.

Pharmacogenomics biomarkers for personalized methadone maintenance treatment: The mechanism and its potential use.

Methadone has a wide pharmacokinetic interindividual variability, resulting in unpredicted treatment response. Pharmacogenomic biomarkers seem promising for personalized methadone maintenance treatment. The evidence supports the use of ABCB1 single-nucleotide polymorphism (SNP) 1236C>T with genotypes C/T or C/C (Jewish) and haplotypes AGCTT carrier, AGCGC heterozygote, or non-carrier (Caucasian), which have a predicted lower methadone dose requirement. In contrast, ABCB1 SNP 1236C>T with genotype T/T (Jewish); haplotypes AGCGC homozygote, AGCTT non-carrier (Caucasian), and ABCB1 3435C>T variant carrier; and haplotypes CGT, TTC, and TGT (Han Chinese) have a predicted higher methadone dose. For methadone plasma levels, ABCB1 diplotype non-CGC/TTT (Malay) predicted lower, and diplotype CGC/TTT (Malay), 3435C>T allelic carrier, haplotypes (CGT, TTC, TGT) (Han Chinese) predicted higher methadone levels. In terms of metabolism biomarkers, a lower methadone requirement was related to carriers of CYP2B6 genotypes *4(G/G) and *9(T/T) among Jewish patients, CYP2B6*9 genotype (T/T) and haplotypes (TA/TG); and CYP2C19 (*2/*2,*2/*3, and *3/*3; Han Chinese). Higher methadone dose was observed in CYP2C19*1 allelic carriers (Han Chinese) and CYP2D6 ultrarapid metabolizer (Caucasian). Lower methadone levels were reported in CYP2B6 SNPs, haplotypes TTT, and AGATAA (Han Chinese), CYP2C19 genotype *1/*1 (Han Chinese), allelic carrier *1xN (Caucasian), and CYP3A4 genotype *1/*1 (Caucasian). Carriers of CYP2B6 genotype *6/*6 (Caucasian), CYP2B6 haplotypes ATGCAG and ATGCTG (Han Chinese), and CYP3A4 genotype *1/*1B (Caucasian) had predicted higher methadone plasma levels. Specific pharmacokinetics biomarkers have potential uses for personalized methadone treatment in specific populations.

Clinical management of chronic mercury intoxication secondary to skin lightening products: A proposed algorithm.

Mercury is a toxic substance that is commonly used in skin lightening products. Various effects on humans have been observed, which affect both users and non-users. Many studies reported delayed diagnosis and treatment, even after weeks of hospitalization. The possible reasons are non-specific clinical manifestation and lack of awareness and knowledge regarding chronic mercury intoxication secondary to skin lightening products. A thorough history of mercury exposure is crucial. Physical assessment and relevant supporting tests are indicated to establish a diagnosis. Blood and urine mercury levels are an essential examination for diagnosis and monitoring of the progress and response to treatment. The primary treatment is the discontinuation of the skin lightening products. Chelation therapy is not mandatory and is usually indicated for symptomatic patients. The prognosis depends on the duration of the product use, concentration of mercury in the skin product, and the severity of clinical presentation.

A Review of the Potential Application of Osteocyte-Related Biomarkers, Fibroblast Growth Factor-23, Sclerostin, and Dickkopf-1 in Predicting Osteoporosis and Fractures.

Bone turnover markers (BTMs) derived from the secretory activities of osteoblasts and the matrix-degrading activities of osteoclasts are useful in monitoring the progression of osteoporosis and the efficacy of anti-osteoporotic treatment. However, the usefulness of BTMs in predicting osteoporosis remains elusive. Osteocytes play a central role in regulating bone formation and resorption. The proteins secreted by osteocytes, such as fibroblast growth factor-23 (FGF23), sclerostin (SOST), and dickkopf-1 (DKK1), could be candidates for osteoporosis screening and fracture prediction. This review summarizes the current evidence on the potential of osteocyte-related proteins as biomarkers for osteoporosis and fracture prediction. The literature reports that SOST may be a potential marker for osteoporosis screening but not for fracture prediction. FGF23 is a potential marker for increased fracture risk, but more studies are needed to confirm its usefulness. The role of DKK1 as a marker to predict osteoporosis and fracture risk cannot be confirmed due to a lack of consistent evidence. In conclusion, circulating osteocyte markers are potential osteoporosis biomarkers, but more studies are warranted to validate their clinical use.

Sexual Inactivity in Methadone Maintenance Treatment Patients.

Sexual dysfunction has been extensively studied in methadone maintenance treatment (MMT) patients. However, little data is available regarding sexual inactivity in the MMT patient population. The objectives of this study were to determine the prevalence and putative risk factors for sexual inactivity in the MMT patient population. This cross-sectional study involved 25-71 year old MMT patients recruited from six methadone clinics. Two hundred and seventy-one patients were interviewed for demographic characteristics, comorbidities, concurrent medications used, and sexual activity. The prevalence of sexual inactivity in the MMT population was found to be 47.6%. Increasing age (p < 0.01) and being single/divorced (p < 0.01) were significantly associated with sexual inactivity. In subgroup analysis, increasing age was significantly associated with sexual inactivity in both single/divorced (p < 0.05) and married (p < 0.05) subgroups, while unemployment (p < 0.05) was only significantly associated with sexual inactivity in the earlier subgroup. Our results suggest that sexual inactivity is common in the MMT patient population. The putative risk factors are related to biological and sociocultural factors. Having specific comorbidities or being on certain medications were not correlated with sexual inactivity in the MMT population. Routine assessment of sexual problems is essential, and proper management should be performed for MMT patients.

Health-Seeking Behavior for Erectile Dysfunction in Methadone Maintenance Treatment Patients.

Background: Erectile dysfunction (ED) is commonly associated with methadone usage. However, little data is known regarding the health-seeking behavior for ED in the methadone maintenance treatment (MMT) population. This study aimed to determine the health-seeking behavior of MMT patients with ED who perceived themselves as having ED. We aimed to assess the attitudes and health-seeking behavior, the effectiveness of the treatment and the factors associated with treatment-seeking behavior. Methods: This was an observational questionnaire-based study. Patients were first screened for ED (n = 154) using the International Index of Erectile Function-5 (IIEF-5). Fifty patients with ED were evaluated for health-seeking behavior for ED. Results: More than half of the patients who thought they had ED (78%) believed their sex life was affected. Most patients (48%) did not seek any information regarding ED. Education level (p = 0.017) and marital status (p = 0.008) were predictive factors of health-seeking behavior. Conclusions: The health-seeking rate among MMT patients with ED needs to be improved. Measures to increase awareness of ED in MMT patients should be taken to overcome the barrier to health-seeking behavior. Health practitioners should take action to screen ED in this population to increase the detection rate and offer appropriate management according to the patients' needs.