Pharmacological Significance of Heme Oxygenase 1 in Prostate Cancer.

Heme oxygenase 1 (HO-1) is a detoxifying antioxidant microsomal enzyme that regulates inflammation, apoptosis, cell proliferation, and angiogenesis in prostate cancer (PCa). This makes HO-1 a promising target for therapeutic prevention and treatment due to its anti-inflammatory properties and ability to control redox homeostasis. Clinical evidence highlights the possible correlation between HO-1 expression and PCa growth, aggressiveness, metastasized tumors, resistance to therapy, and poor clinical outcomes. Interestingly, studies have reported anticancer benefits mediated by both HO-1 induction and inhibition in PCa models. Contrasting evidence exists on the role of HO-1 in PCa progression and possible treatment targets. Herein, we provide an overview of available evidence on the clinical significance of HO-1 signaling in PCa. It appears that the beneficial effects of HO-1 induction or inhibition are dependent on whether it is a normal versus malignant cell as well as the intensity (major vs. minor) of the increase in HO-1 enzymatic activity. The current literature evidence indicates that HO-1 has dual effects in PCa. The amount of cellular iron and reactive oxygen species (ROS) can determine the role of HO-1 in PCa. A major increase in ROS enforces HO-1 to a protective role. HO-1 overexpression may provide cryoprotection to normal cells against oxidative stress via suppressing the expression of proinflammatory genes, and thus offer therapeutic prevention. In contrast, a moderate increase in ROS can lead to the perpetrator role of HO-1, which is associated with PCa progression and metastasis. HO-1 inhibition by xenobiotics in DNA-damaged cells tilts the balance to promote apoptosis and inhibit PCa proliferation and metastasis. Overall, the totality of the evidence revealed that HO-1 may play a dual role in the therapeutic prevention and treatment of PCa.

Association Between Vitamin D Levels and Inflammatory Markers in COVID-19 Patients: A Meta-Analysis of Observational Studies.

PURPOSE: Vitamin D has immunomodulatory properties that can be useful in COVID-19 patients. We performed a meta-analysis of observational studies to analyze the association of vitamin D levels with the inflammatory markers in COVID-19 patients. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Database of Systematic Reviews, and ClinicalTrial.gov for any relevant studies with comparison data reporting vitamin D levels and inflammatory markers in COVID-19 patients. A literature search was conducted from December 1, 2019, to January 14, 2022. Vitamin D deficiency was defined by each individual study and ranged from <9.9 ng/mL to <30 ng/mL. The inflammatory markers of interest were interleukin-6 (IL-6), C-reactive protein (CRP), ferritin, procalcitonin, erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), fibrinogen and D-dimer. Weighted mean difference (WMD) and 95% confidence intervals (CIs) were pooled using random or fixed-effects models. Two independent investigators assessed study eligibility and synthesized the evidence. RESULTS: Thirty-two observational studies were included comprising of 7,771 patients ranging from 40-81 years of age with 57.1% being male. Meta-analysis showed that patients that were vitamin D sufficient (levels >30ng/mL) had statistically significant lower levels of IL-6, CRP, ferritin, LDH, fibrinogen, and D-dimer compared to vitamin D deficient group. With the highest mean difference found in ferritin (95.62; 95% CI, 33.14-158.10); P=0.003; I2=99%). No significant reductions were found in ESR (P=0.97). All inflammatory markers analyzed were higher than the normal healthy reference ranges in both groups. CONCLUSIONS: Our results suggest that low vitamin D levels are associated with increased inflammatory marker levels. Vitamin D deficiency may potentially serve as an early identifier for COVID-19 patients at high risk of developing severe inflammatory conditions as well as thrombotic complications. Randomized controlled trials should be conducted to establish a causal relationship.

Examining Liver Function in Adults with Diabetes in the United States.

PURPOSE: Hyperglycemia is the hallmark of various types of diabetes and considered to be a risk factor for several chronic disorders including liver function. Though liver is a dynamic organ, incessant glucotoxicity can lead to altered liver function. The goals of the present study were to examine the association between diabetes with liver functions amongst adults in the United States. METHODS: We analyzed 14,948 adults with diabetes in the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2016. Diabetes and prediabetes were defined in accordance with the American Diabetes Association 2021 guidelines. The association of demographic characteristics with glycemic levels was analyzed using the Chi-square test. A multivariate logistic regression model was constructed to evaluate the associations of glycemic levels with abnormal liver enzyme levels. Regression model was adjusted for age, sex, and ethnicity. The statistical analyses were performed using STATA ver. 14. A. p value of ≤0.05 or≤0.001 was considered statistically significant. RESULTS: A total of 14,948 adults (20 years and above) were included in this study. Sample mean age was 45.5±0.33 yrs., 54% were female, 53% were non-Hispanic White, and 60% had some college or graduate level education. In the overall sample, 19% adults were diabetic and 34% were pre-diabetic. Pre-diabetic glycemic levels were associated over one and half times higher odds of ALT (OR: 1.45, 95% CI: 1.31, 1.60, p<0.001) and over 1.3 times of higher odds AST (OR: 1.30, 95% CI: 1.14, 1.49,p<0.001). On the other hand, diabetic glycemic levels were associated with close to one and half times higher odds of ALT (OR: 1.37, 95% CI: 1.18, 1.59,p<0.001) and AST (OR: 1.48, 95% CI: 1.24, 1.76, p<0.001). On regression analysis, after adjustment, pre-diabetic and diabetic status was associated with high ALT (OR: 1.21, 95%CI: 1.11, 1.32, p<0.001), AST (OR: 1.14, 95%CI: 1.04, 1.27, p<0.05), ALP (OR: 1.40, 95%CI: 1.16, 1.68, p<0.001) and GGT (OR: 1.42, 95%CI: 1.24, 1.63, p<0.001). CONCLUSIONS: Our results indicated that diabetes is significantly associated with liver function. This observed association deserves further exploration to understand the longitudinal impact of diabetes on liver function.

Simulation of Remdesivir Pharmacokinetics and Its Drug Interactions.

PURPOSE: Remdesivir, a drug originally developed against Ebola virus, is currently recommended for patients hospitalized with coronavirus disease of 2019 (COVID-19). In spite of United States Food and Drug Administration's recent assent of remdesivir as the only approved agent for COVID-19, there is limited information available about the physicochemical, metabolism, transport, pharmacokinetic (PK), and drug-drug interaction (DDI) properties of this drug. The objective of this in silico simulation work was to simulate the biopharmaceutical and DDI behavior of remdesivir and characterize remdesivir PK properties in special populations which are highly affected by COVID-19. METHODS: The Spatial Data File format structures of remdesivir prodrug (GS-5734) and nucleoside core (GS-441524) were obtained from the PubChem database to upload into the GastroPlus software 9.8 version (Simulations Plus Inc., USA). The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules of GastroPlus were used to simulate physicochemical and PK properties, respectively, in healthy and predisposed patients. Physiologically based pharmacokinetic (PBPK) modeling of GastroPlus was used to simulate different patient populations based on age, weight, liver function, and renal function status. Subsequently, these data were used in the Drug-Drug Interaction module to simulate drug interaction potential of remdesivir with other COVID-19 drug regimens and with agents used for comorbidities. RESULTS: Remdesivir nucleoside core (GS-441524) is more hydrophilic than the inactive prodrug (GS-5734) with nucleoside core demonstrating better water solubility. GS-5734, but not GS-441524, is predicted to be metabolized by CYP3A4. Remdesivir is bioavailable and its clearance is achieved through hepatic and renal routes. Differential effects of renal function, liver function, weight, or age were observed on the PK profile of remdesivir. DDI simulation study of remdesivir with perpetrator drugs for comorbidities indicate that carbamazepine, phenytoin, amiodarone, voriconazole, diltiazem, and verapamil have the potential for strong interactions with victim remdesivir, whereas agents used for COVID-19 treatment such as chloroquine and ritonavir can cause weak and strong interactions, respectively, with remdesivir. CONCLUSIONS: GS-5734 (inactive prodrug) appears to be a superior remdesivir derivative due to its hepatic stability, optimum hydrophilic/lipophilic balance, and disposition properties. Remdesivir disposition can potentially be affected by different physiological and pathological conditions, and by drug interactions from COVID-19 drug regimens and agents used for comorbidities.

Steroidogenesis in Peripheral and Transition Zones of Human Prostate Cancer Tissue.

The peripheral zone (PZ) and transition zone (TZ) represent about 70% of the human prostate gland with each zone having differential ability to develop prostate cancer. Androgens and their receptor are the primary driving cause of prostate cancer growth and eventually castration-resistant prostate cancer (CRPC). De novo steroidogenesis has been identified as a key mechanism that develops during CRPC. Currently, there is very limited information available on human prostate tissue steroidogenesis. The purpose of the present study was to investigate steroid metabolism in human prostate cancer tissues with comparison between PZ and TZ. Human prostate cancer tumors were procured from the patients who underwent radical prostatectomy without any neoadjuvant therapy. Human prostate homogenates were used to quantify steroid levels intrinsically present in the tissues as well as formed after incubation with 2 µg/mL of 17-hydroxypregnenolone (17-OH-pregnenolone) or progesterone. A Waters Acquity ultraperformance liquid chromatography coupled to a Quattro Premier XE tandem quadrupole mass spectrometer using a C18 column was used to measure thirteen steroids from the classical and backdoor steroidogenesis pathways. The intrinsic prostate tissue steroid levels were similar between PZ and TZ with dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), pregnenolone and 17-OH-pregnenolone levels higher than the other steroids measured. Interestingly, 5-pregnan-3,20-dione, 5-pregnan-3-ol-20-one, and 5-pregnan-17-ol-3,20-dione formation was significantly higher in both the zones of prostate tissues, whereas, androstenedione, testosterone, DHT, and progesterone levels were significantly lower after 60 min incubation compared to the 0 min control incubations. The incubations with progesterone had a similar outcome with 5-pregnan-3,20-dione and 5-pregnan-3-ol-20-one levels were elevated and the levels of DHT were lower in both PZ and TZ tissues. The net changes in steroid formation after the incubation were more observable with 17-OH-pregnenolone than with progesterone. In our knowledge, this is the first report of comprehensive analyses of intrinsic prostate tissue steroids and precursor-driven steroid metabolism using a sensitive liquid chromatography-mass spectrometry assay. In summary, the PZ and TZ of human prostate exhibited similar steroidogenic ability with distinction in the manner each zone utilizes the steroid precursors to divert the activity towards backdoor pathway through a complex matrix of steroidogenic mechanisms.

Association Between Polymorphisms in Cytokine Gene and Viral Infections in Renal and Liver Transplant Recipients: A Systematic Review.

PURPOSE: Although transplantations are associated with an increased risk of post-transplantation infections, they greatly improve life expectancy and patients' quality of life. Cytokine genes play an important role in the success of transplants due to their immunological functions. A systematic review was conducted to evaluate cytokine gene polymorphisms and risk of cytomegalovirus (CMV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in kidney and liver transplant recipients. METHODS: A systematic search was conducted using PubMed, EMBASE, Medline and Google Scholar from their inception until January 28, 2019 using appropriate key words. Review articles, case reports or series, studies conducted on non-human subjects and published in languages other than English were excluded. Data were abstracted using a standardized form. The quality of the studies included was assessed using "Risk of Bias Assessment tool for Non-randomized Studies (RoBANS)". RESULTS: Thirty-one studies met our inclusion criteria; populations studied were diverse with a sample ranging from 20 to 1,671. Nineteen studies evaluated Interleukin (IL)-28B polymorphism, while six studies evaluated interferon lambda (IFN-λ) gene polymorphisms and their impact on CMV, HCV, and HBV progression. Polymorphisms in IL-10 gene were investigated in six studies. Polymorphisms in IL-12B and IL-1B gene were associated with a higher risk of developing CMV infections while polymorphisms in IL-28B were associated with a lower incidence of CMV infection in renal transplant recipients. Similarly, polymorphisms in IL-28B were associated with higher liver dysfunction from HBV infection in liver transplant recipients. Studies included had low risk of bias. CONCLUSIONS: Cytokine gene polymorphisms IL-12B and IL-1B were found to be associated with an increased risk of infection in kidney transplants and IL-28B in liver transplant recipients. However, the small number and heterogeneity of studies limits the generalization of our results. Further research may lead to finding these associations in larger studies which perhaps improve the use of genetic testing and targeted antiviral therapy. This will further reduce the risk of viral infections associated with cytokine gene polymorphisms in post renal and liver transplant recipients.

Assessing the Elevation of Cardiac Biomarkers and the Severity of COVID-19 Infection: A Meta-analysis.

- Purpose: Since December 2019, coronavirus disease 2019 infection has become a global pandemic. The cases of Coronavirus Disease 2019 (COVID-19)-related acute cardiac injury with unknown pathophysiologic mechanism has become increasingly prevalent. However, it is not yet understood how the extent of cardiac injury differs with the intensity of viral infection.  In the current study, we aimed to assess the association between elevated cardiac biomarkers and the severity of COVID-19 infection. METHODS: A systematic literature search was performed across PubMed and Embase databases from December 1, 2019 to July 10, 2020, to identify studies that reported cardiac biomarkers of troponin (TnI) and creatine kinase-myocardial band (CK-MB) in patients with COVID-19. These studies compared non-severe patients with severe patients, or survivors with non-survivors or medical patients with critically ill patients. The data were extracted for TnI, CK-MB, N-terminal-brain natriuretic peptide (NT-BNP), D-dimer, and lactate dehydrogenase (LDH), C-reactive protein (CRP), and interleukin 6 (IL-6). Wherever possible, the data were pooled for meta-analysis (Review Manager, RevMan. version 5.3) with standard or weighted mean or median difference and corresponding 95% confidence intervals (95% CI). RESULTS: A total of 25 studies involving 5,626 patients were included in the present analysis. More severe COVID-19 infection was found to be associated with higher mean values of TnI (-0.54 [-0.72, -0.36]) (ng/mL), CK-MB (-1.55 [-2.23, -0.88]) (ng/mL) and (-4.75 [-13.31, 3.82]) (units/L), NT-BNP (-815.7 [-1073.97, -557.42]) (pg/mL), D-dimer (-1.4 [-2.04, -0.77]) (mcg/mL), and LDH (-176.59 [-224.11, -129.06]) (units/L), as well as CRP (-64.03 [-68.88, -59.19]) (mg/L) and IL-6 (-22.59 [-29.39, -15.79]) (pg/mL). CONCLUSIONS: There is significant association between elevated cardiac biomarkers and the severity of COVID-19, which underlines the increased risk of acute cardiac injury with more severe viral infection. This highlights the need to understand the cardiac history among the COVID-19 patients during initial assessment and for monitoring.

Identification of human cytochrome P450 enzymes involved in the hepatic and intestinal biotransformation of 20(S)-protopanaxadiol.

20(S)-Protopanaxadiol (aPPD), a ginseng sapogenin, has been shown to be a promising anti-cancer compound and anti-depressant agent. Although the bacterial biotransformation of ginsenosides has been studied thoroughly, few have reported on the cytochrome P450 (P450) mediated metabolism of aPPD. Taken orally, aPPD must first undergo absorption and metabolism in the intestine before further metabolism in the liver. The present study investigated the comparative biotransformation profile of aPPD in human intestinal microsomes (HIM) and human liver microsomes (HLM) and characterized the human P450 enzymes involved in aPPD metabolism. Three major monooxygenated metabolites and five minor dioxygenated metabolites were identified as the predominant products in aPPD incubations with HIM and HLM using liquid chromatography-mass spectrometry. Reaction phenotyping studies were performed with a panel of specific P450 chemical inhibitors, antibody inhibition and human recombinant P450 enzymes. Ketoconazole, a CYP3A inhibitor, blocked the formation of oxygenated metabolites of aPPD in both HIM and HLM in a concentration dependent manner. Among the human recombinant P450 enzymes assayed, CYP3A4 exhibited the highest activity towards aPPD oxidative metabolite formation, followed by CYP3A5. In summary, the results have shown that aPPD is extensively metabolized by HIM and the metabolite profile following in vitro incubations is similar in HIM and HLM. CYP3A4 and CYP3A5 isoforms are the predominant enzymes responsible for oxygenation of aPPD in HIM and HLM. The characterization of aPPD as a CYP3A substrate may facilitate better prediction of drug-herb interactions when aPPD is taken concomitantly with other therapeutic agents.

Significance of Chalcone Scaffolds in Medicinal Chemistry.

Chalcone is a simple naturally occurring α,ß-unsaturated ketone with biological importance, which can also be easily synthesized in laboratories by reaction between two aromatic scaffolds. In plants, chalcones occur as polyphenolic compounds of different frameworks which are bioactive molecules that have been in traditional medicinal practice for many years. Chalcone-based lead molecules have been developed, possessing varied potentials such as antimicrobial, antiviral, anti-inflammatory, anticancer, anti-oxidant, antidiabetic, antihyperurecemic, and anti-ulcer effects. Chalcones contribute considerable fragments to give important heterocyclic molecules with therapeutic utilities targeting various diseases. These characteristic features have made chalcone a topic of interest among researchers and have attracted investigations into this widely applicable structure. This review highlights the extensive exploration carried out on the synthesis, biotransformations, chemical reactions, hybridization, and pharmacological potentials of chalcones, and aims to provide an extensive, thorough, and critical review of their importance, with emphasis on their properties, chemistry, and biomedical applications to boost future investigations into this potential scaffold in medicinal chemistry.

Clinical Outcomes among Hospitalized COVID-19 Patients Who Received Baricitinib or Tocilizumab in Addition to Standard of Care.

COVID-19 infection is caused by the novel severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2). This novel virus has transformed into different resistant variants (e.g., omicron; delta; alpha; epsilon) since its first emergence in 2019. The National Institutes of Health and Infectious Diseases Society of America guidelines currently recommend adding either baricitinib or tocilizumab to the standard of care for severe COVID-19 treatment. An outcome comparison between baricitinib and tocilizumab is needed to determine which agent is more appropriate and safer in clinical practice when deciding treatment. We aimed to compare mortality and clinical outcomes between tocilizumab and baricitinib in the management of severe COVID-19 infection. A total of 5638 adult patients from 16 acute care hospitals in a large healthcare system in Texas were included in this multicentered retrospective cohort study. The median age of the patients was 56 years and 46.67% of them were female. Severe COVID-19 patients were treated with standard of care and either tocilizumab or baricitinib. The primary outcome of hospital admission mortality rates was found to be higher with tocilizumab (odd ratio (OR) of 1.56; p = 0.001; 95% CI 1.19 to 2.008) compared to that with baricitinib (OR 0.65; p = 0.001; 95% CI 0.50 to 0.84). For one of the secondary outcomes, patients who received tocilizumab were 3.75 times more likely to be admitted to the ICU than those receiving baricitinib (p = 0.001; 95% CI 2.89 to 4.85). Among the 1199 COVID-19 patients who were admitted to the ICU, the ICU length of stay was shorter among patients receiving baricitinib with a mean difference of 4.42 days and a median difference of 2.54 days, compared to those receiving tocilizumab (p < 0.0001; 95% CI -5.97 to -2.62) as another secondary outcome. Our large retrospective observational study showed that baricitinib reduced mortality; the likelihood of ICU admission; and the ICU length of stay compared to tocilizumab in patients with severe COVID-19 infection.

ADME Gene-Related Pharmacogenomic Labeling of FDA-Approved Drugs: Comparison with Clinical Pharmacogenetics Implementation Consortium (CPIC) Evidence Levels.

Pharmacogenomics (PGx) can facilitate the transition to patient-specific drug regimens and thus improve their efficacy and reduce toxicity. The aim of this study was to evaluate the overlap of PGx classification for drug absorption, distribution, metabolism, and elimination (ADME)-related genes in the U.S. Food and Drug Administration (FDA) PGx labeling and in the Clinical Pharmacogenetics Implementation Consortium (CPIC) database. FDA-approved drugs and PGx labeling for ADME genes were identified in the CPIC database. Drugs were filtered by their association with ADME (pharmacokinetics)-related genes, PGx FDA labeling class, and CPIC evidence level. FDA PGx labeling was classified as either actionable, informative, testing recommended, or testing required, and varying CPIC evidence levels as either A, B, C, or D. From a total of 442 ADME and non-ADME gene-drug pairs in the CPIC database, 273, 55, and 48 pairs were excluded for lack of FDA labeling, mixed CPIC evidence level provisional classification, and non-ADME gene-drug pairs, respectively. The 66 ADME gene-drug pairs were classified into the following categories: 10 (15%) informative, 49 (74%) actionable, 6 (9%) testing recommended, and 1 (2%) testing required. CYP2D6 was the most prevalent gene among the FDA PGx labeling. From the ADME gene-drug pairs with both FDA and CPIC PGx classification, the majority of the drugs were for depression, cancer, and pain medications. The ADME gene-drug pairs with FDA PGx labeling considerably overlap with CPIC classification; however, a large number of ADME gene-drug pairs have only CPIC evidence levels but not FDA classification. PGx actionable labeling was the most common classification, with CYP2D6 as the most prevalent ADME gene in the FDA PGx labeling. Health professionals can impact therapeutic outcomes via pharmacogenetic interventions by analyzing and reconciling the FDA labels and CPIC database.

Evaluation of agreement between a noninvasive method for real-time measurement of critical blood values with a standard point-of-care device.

The purpose of this work was to investigate the degree of agreement between two distinct approaches for measuring a set of blood values and to compare comfort levels reported by participants when utilizing these two disparate measurement methods. Radial arterial blood was collected for the comparator analysis using the Abbott i-STAT® POCT device. In contrast, the non-invasive proprietary DBC methodology is used to calculate sodium, potassium, chloride, ionized calcium, total carbon dioxide, pH, bicarbonate, and oxygen saturation using four input parameters (temperature, hemoglobin, pO2, and pCO2). Agreement between the measurement for a set of blood values obtained using i-STAT and DBC methodology was compared using intraclass correlation coefficients, Passing and Bablok regression analyses, and Bland Altman plots. A p-value of <0.05 was considered statistically significant. A total of 37 participants were included in this study. The mean age of the participants was 42.4 ± 13 years, most were male (65%), predominantly Caucasian/White (75%), and of Hispanic ethnicity (40%). The Intraclass Correlation Coefficients (ICC) analyses indicated agreement levels ranging from poor to moderate between i-STAT and the DBC's algorithm for Hb, pCO2, HCO3, TCO2, and Na, and weak agreement for pO2, HSO2, pH, K, Ca, and Cl. The Passing and Bablok regression analyses demonstrated that values for Hb, pO2, pCO2, TCO2, Cl, and Na obtained from the i-STAT did not differ significantly from that of the DBC's algorithm suggesting good agreement. The values for Hb, K, and Na measured by the DBC algorithm were slightly higher than those obtained by the i-STAT, indicating some systematic differences between these two methods on Bland Altman Plots. The non-invasive DBC methodology was found to be reliable and robust for most of the measured blood values compared to invasive POCT i-STAT device in healthy participants. These findings need further validation in larger samples and among individuals afflicted with various medical conditions.

Vitamin D in Melanoma: Potential Role of Cytochrome P450 Enzymes.

Vitamin D is a promising anticancer agent for the prevention and treatment of several cancers, including melanoma. Low 25-hydroxyvitamin D levels, a routinely used marker for vitamin D, have been suggested as one of the factors in the development and progression of melanoma. The parent vitamin D needs activation by cytochrome P450 (CYP) enzymes to exert its actions via the vitamin D receptor (VDR). This review discusses the role of vitamin D in melanoma and how CYP-mediated metabolism can potentially affect the actions of vitamin D. Through interacting with the retinoid X receptor, VDR signaling leads to anti-inflammatory, antioxidative, and anticancer actions. Calcitriol, the dihydroxylated form of vitamin D3, is the most active and potent ligand of VDR. CYP27A1, CYP27B1, and CYP2R1 are involved in the activation of vitamin D, whereas CYP24A1 and CYP3A4 are responsible for the degradation of the active vitamin D. CYP24A1, the primary catabolic enzyme of calcitriol, is overexpressed in melanoma tissues and cells. Several drug classes and natural health products can modulate vitamin D-related CYP enzymes and eventually cause lower levels of vitamin D and its active metabolites in tissues. Although the role of vitamin D in the development of melanoma is yet to be fully elucidated, it has been proposed that melanoma prevention may be significantly aided by increased vitamin D signaling. Furthermore, selective targeting of the catabolic enzymes responsible for vitamin D degradation could be a plausible strategy in melanoma therapy. Vitamin D signaling can be improved by utilizing dietary supplements or by modulating CYP metabolism. A positive association exists between the intake of vitamin D supplements and improved prognosis for melanoma patients. Further investigation is required to determine the function of vitamin D supplementation and specific enzyme targeting in the prevention of melanoma.

Investigating the Efficacy of EGFR-TKIs and Anti-VEGFR Combination in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis.

INTRODUCTION: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with anti-vascular endothelial growth factor receptor (VEGFR) agents have shown improved survival outcomes in recent studies. However, its efficacy related to survival outcomes as a first- or second-line agent and based on generations remains to be explored. This study estimated the survival outcomes of EGFR-TKIs plus anti-VEGFR in combination in defined populations of advanced non-small cell lung cancer (NSCLC) patients overall, as a first- or second line of treatment, with different generations of EGFR-TKIs and EGFR-TKIs plus bevacizumab combination as a subgroup. METHODS: A literature search was conducted using PubMed, SCOPUS, Cochrane Library, and ClinicalTrials.gov databases through June 2023 to identify primary research reporting the survival outcomes of EGFR-TKIs in combination with anti-VEGFR agents in patients with advanced NSCLC. Studies that were single-arm, published in non-English languages, and had missing data on survival outcomes were excluded. A meta-analysis was conducted to generate pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS). Methodological quality and risk of bias in studies were assessed using the Cochrane Handbook for Systematic Reviews of Interventions risk of bias tool. RESULTS: A total of 20 randomized controlled trials were included in the qualitative synthesis, and 11 (2182 participants) were included in the meta-analysis. Patients' median age ranged from 58 to 68 years; 36% to 70% of patients were female; most of them had IIIa/b to IV stage cancer. In meta-analyses, the EGFR-TKIs plus anti-VEGFR combination resulted in improved PFS (HR, 0.73; 95% CI: 0.61, 0.86; p < 0.00001) in patients with advanced NSCLC but had no impact on OS (HR, 0.93; 95% CI: 0.79, 1.10; p = 0.41). The first line of treatment and first-generation EGFR-TKIs with the combination also improved the PFS (HR, 0.64; 95% CI: 0.57, 0.71; p < 0.00001; HR, 0.63; 95% CI: 0.56, 0.71; p < 0.00001) respectively, however, had no impact on OS. CONCLUSIONS: Our meta-analysis indicated EGFR-TKIs with anti-VEGFR in combination not only improved overall PFS but also showed similar results to a first line and first-generation agent compared to EGFR-TKI alone.

Simulation of drug-drug interactions between breast cancer chemotherapeutic agents and antiemetic drugs.

BACKGROUND: Chemotherapy-induced nausea and vomiting are commonly experienced side effects in breast cancer (BCa) patients. Antiemetic drugs used in BCa treatment are either inhibitors or inducers of cytochrome P450 (CYP) enzymes, while anticancer drugs are metabolized by CYPs. OBJECTIVES: The purpose of the present work was to evaluate in silico drug-drug interaction (DDI) potential between BCa chemotherapeutic drugs and antiemetic agents. METHODS: The Drug-Drug Interaction™ module of GastroPlus™ was employed to assess CYP-related interactions between antiemetic and anticancer therapy combinations. The CYP inhibitory or inducing parameters (IC50, Ki, EC50) used in simulations were obtained from the literature. RESULTS: Analyses of twenty-three BCa drugs indicated that 22% of the chemotherapeutic drugs do not need an antiemetic agent due to their low emetogenicity, whereas 30% of the anticancer drugs are not metabolized by CYPs. The remaining eleven anticancer drugs metabolized by CYPs generated ninety-nine combinations with nine antiemetics. Simulation of DDIs suggest that about half of the pairs did not demonstrate any potential for DDI, whereas 30%, 10%, and 9% of the pairs showed weak, moderate, and strong interaction potential, respectively. In the present study, netupitant was the only antiemetic that showed strong inhibitory interactions (predicted AUC ratio > 5) with CYP3A4-metabolzied anticancer therapies (e.g., docetaxel, ribociclib, olaparib). Moderate to no interactions were observed with ondansetron, aprepitant, rolapitant, and dexamethasone in combination with anticancer agents. CONCLUSION: It is critical to recognize that these interactions can get amplified in cancer patients because of the severity of the disease and chemotherapy toxicities. Clinicians need to be aware of the DDI likelihood of the drug combinations used in BCa treatment.

SGLT2 Inhibitors as Potential Anticancer Agents.

Sodium-glucose cotransporter 2 (SGLT2) serves as a critical glucose transporter that has been reported to be overexpressed in cancer models, followed by increased glucose uptake in both mice and humans. Inhibition of its expression can robustly thwart tumor development in vitro and in vivo. SGLT2 inhibitors are a comparatively new class of antidiabetic drugs that have demonstrated anticancer effects in several malignancies, including breast, liver, pancreatic, thyroid, prostate, and lung cancers. This review aims to assess the extent of SGLT involvement in different cancer cell lines and discuss the pharmacology, mechanisms of action, and potential applications of SGLT2 inhibitors to reduce tumorigenesis and its progression. Although these agents display a common mechanism of action, they exhibit distinct affinity towards the SGLT type 2 transporter compared to the SGLT type 1 transporter and varying extents of bioavailability and half-lives. While suppression of glucose uptake has been attributed to their primary mode of antidiabetic action, SGLT2 inhibitors have demonstrated several mechanistic ways to combat cancer, including mitochondrial membrane instability, suppression of ß-catenin, and PI3K-Akt pathways, increase in cell cycle arrest and apoptosis, and downregulation of oxidative phosphorylation. Growing evidence and ongoing clinical trials suggest a potential benefit of combination therapy using an SGLT2 inhibitor with the standard chemotherapeutic regimen. Nevertheless, further experimental and clinical evidence is required to characterize the expression and role of SGLTs in different cancer types, the activity of different SGLT subtypes, and their role in tumor development and progression.

Evaluation of pharmacogenomic evidence for drugs related to ADME genes in CPIC database.

OBJECTIVES: Clinical Pharmacogenetics Implementation Consortium (CPIC) is a platform that advances the pharmacogenomics (PGx) practice by developing evidence-based guidelines. The purpose of this study was to analyze the CPIC database for ADME related genes and their corresponding drugs, and evidence level for drug-gene pairs; and to determine the presence of these drug-gene pairs in the highest mortality diseases in the United States. METHODS: CPIC database was evaluated for drug-gene pairs related to absorption, distribution, metabolism, and excretion (ADME) properties. National Vital Statistics from Centers for Disease Control and Prevention was used to identify the diseases with the highest mortality. CPIC levels are assigned to different drug-gene pairs based on varying levels of evidence as either A, B, C, or D. All drug-gene pairs assigned with A/B, B/C, or C/D mixed levels were excluded from this study. A stepwise exclusion process was followed to determine the prevalence of various ADME drug-gene pairs among phase I/II enzymes or transporters and stratify the drug-gene pairs relevant to different disease conditions most commonly responsible for death in the United States. RESULTS: From a total of 442 drug-gene pairs in the CPIC database, after exclusion of 86 drug-gene pairs with levels A/B, B/C, or C/D, and 211 non-ADME related genes, 145 ADME related drug-gene pairs resulted. From the 145 ADME related drug-genes pairs, the following were the distribution of levels: Level A: 43 (30%), Level B: 22 (15%), Level C: 59 (41%), Level D: 21 (14%). The most prevalent ADME gene with CPIC level A classification was cytochrome P450 2C9 (CYP2C9) (26%) and overall, the most prevalent ADME gene in the CPIC database was CYP2D6 (30%). The most prevalent diseases related to the CPIC evidence related drugs were cancer and depression. CONCLUSIONS: We found that there is an abundance of ADME related genes in the CPIC database, including in the high mortality disease states of cancer and depression. There is a differential level of pharmacogenomic evidence in drug-gene pairs enlisted in CPIC where levels A and D having the greatest number of drug-gene pairs. CYP2D6 was the most common ADME gene with CPIC evidence for drug-gene pairs. Pharmacogenomic applications of CPIC evidence can be leveraged to individualize patient therapy and lower adverse effect events.

Effect of gut microbiome on serotonin metabolism: a personalized treatment approach.

Several factors including diet, exercise, and medications influence the makeup of the resilient but adaptable gut microbiome. Bacteria in the gut have a significant role in the homeostasis of the neurotransmitter serotonin, also known as 5-hydroxytryptamine, involved in mood and behavior. The goal of the current work is to review the effect of the gut microbiome on serotonin metabolism, and how it can potentially contribute to the development of a personalized treatment approach for depression and anxiety. Bacterial strains provide innovative therapeutic targets that can be used for disorders, such as depression, that involve dysregulation of serotonin. Advances in bacterial genomic sequencing have increased the accessibility and affordability of microbiome testing, which unlocks a new targeted pathway to modulate serotonin metabolism by targeting the gut-brain axis. Microbiome testing can facilitate the recommendation of strain-specific probiotic supplements based on patient-specific microbial profiles. Several studies have shown that supplementation with probiotics containing specific species of bacteria, such as Bifidobacterium and Lactobacillus, can improve symptoms of depression. Further research is needed to improve the process and interpretation of microbiome testing and how to successfully incorporate testing results into guiding clinical decision-making. This targeted approach centered around the gut-brain axis can provide a novel way to personalize therapy for mental health disorders.

Pharmacokinetics and pharmacodynamics of Rh2 and aPPD ginsenosides in prostate cancer: a drug interaction perspective.

Ginsenoside Rh2 and its aglycon (aPPD) are one of the major metabolites from Panax ginseng. Preclinical studies suggest that Rh2 and aPPD have antitumor effects in prostate cancer (PCa). Our aims in this review are (1) to describe the pharmacokinetic (PK) properties of Rh2 and aPPD ginsenosides; 2) to provide an overview of the preclinical findings on the use of Rh2 and aPPD in the treatment of PCa; and (3) to highlight the mechanisms of its PK and pharmacodynamic (PD) drug interactions. Increasing evidence points to the potential efficacy of Rh2 or aPPD for PCa treatment. Based on the laboratory studies, Rh2 or aPPD combinations revealed an additive or synergistic interaction or enhanced sensitivity of anticancer drugs toward PCa. This review reveals that enhanced anticancer activities were demonstrated in preclinical studies through interactions of Rh2 and/or aPPD with the proteins related to PK (e.g., cytochrome P450 enzymes, transporters) or PD of the other anticancer drugs or PCa signaling pathways. In conclusion, combining Rh2 or aPPD with anti-prostate cancer drugs leads to PK or PD interactions which could facilitate either therapeutically beneficial or toxic effects.

Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis.

Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administered with abiraterone. The goal of the present study was to understand the effect of dexamethasone on the disposition of abiraterone. Methods: Adult male CD-1 mice were treated with either dexamethasone (80 mg/kg/day) or vehicle for three consecutive days, followed by the administration of a single dose of abiraterone acetate (180 mg/kg) as an oral gavage. Blood samples were collected by tail bleeding at timepoints between 0 to 24 h. Subsequently, abiraterone was extracted from the mouse serum using a neutral pH condition and serum abiraterone levels were determined using a liquid chromatography-mass spectrometry assay. Results: Our results demonstrated that dexamethasone lowered the maximum plasma concentration and area under the curve parameters by approximately five- and ten-fold, respectively. Similar effects were also observed on the plasma half-life and oral clearance parameters. This is the first report of dexamethasone effect on abiraterone disposition in vivo. Conclusions: We conclude that dexamethasone has the potential to reduce the plasma abiraterone level and thus compromise its CYP17A1 inhibitory ability in the procancerous androgen biosynthesis pathway. Thus, use of a higher abiraterone dose may be warranted when used alongside dexamethasone.