Safety, pharmacokinetics and pharmacodynamics of BI 655064 in phase 1 clinical trials in healthy Chinese and Japanese subjects.

AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of BI 655064 in healthy Chinese and Japanese subjects after administration of single doses of 80-240 mg and multiple dosing of 240 mg once weekly over 4 weeks. METHODS: Two phase 1, double-blind, placebo-controlled studies were conducted (single-rising doses of BI 655064 in Chinese/Japanese male subjects [n = 12 per BI 655064 dose group] or repeated 240 mg BI 655064 in Chinese male subjects [n = 9]). Plasma samples were collected to investigate BI 655064 pharmacokinetics, pharmacodynamics (CD40 receptor occupancy [RO]) and immunogenicity, along with the safety and tolerability of BI 655064. RESULTS: BI 655064 showed good overall tolerability following single-dose administration of 80-240 mg and repeated administration of 240 mg BI 655064 over 4 weeks. More Chinese subjects reported adverse events compared with Japanese subjects following single-dose administration (59.4% vs 3.1%). BI 655064 exhibited nonlinear, saturable kinetics, with higher doses resulting in slower apparent clearance (0.514-0.713 mL min-1 ), and disproportionately higher total exposure (AUC0-inf ; 5610-7780 µg·h mL-1 ) and maximum plasma concentration (15 700-21 300 ng mL-1 ) with 240 mg BI 655064. Ninety percent inhibition of CD40 RO was achieved with doses ≥120 mg, and a direct relationship between BI 655064 plasma concentration and inhibition of CD40 RO was observed. Most subjects had a positive treatment-emergent antidrug antibody response. CONCLUSIONS: BI 655064 pharmacokinetic and safety profiles in East Asian male subjects were consistent with those observed in a Western population. No adjustments in the BI 655064 dosing recommendations are warranted for future clinical trials.

Sequential therapy involving an early switch from entecavir to pegylated interferon-α in Japanese patients with chronic hepatitis B.

AIM: The optimal combination of two currently available agents with different mechanisms of action, a nucleos(t)ide analog and pegylated interferon-α (PegIFNα), must be determined to improve treatment of chronic hepatitis B (CHB). METHODS: In this study, 24 patients with CHB (14 hepatitis B envelope antigen [HBeAg]-positive patients and 10 HBeAg-negative patients) received entecavir for 36-52 weeks, followed by entecavir plus Peg-IFNα2a for 4 weeks, and finally by PegIFNα-2a alone for 44 weeks. RESULTS: A sustained biochemical, virologic, and serologic response was obtained in 7/24 (29%) patients at 48 weeks post-treatment (2/14 [14%] in HBeAg-positive vs 5/10 [50%] in HBeAg-negative patients, P = 0.085). At baseline, patients with a sustained response had a significantly lower γ-glutamyl transferase level (P = 0.0023), a lower aspartate aminotransferase-to-platelet ratio index (P = 0.049), and a lower α-fetoprotein level (P = 0.042) than those without a sustained response. The decline in hepatitis B surface antigen (HBsAg) levels during the first 24 weeks of PegIFNα-2a treatment in patients with a sustained response was greater than that in patients without (P = 0.017). Additionally, HBsAg seroclearance was achieved in two patients (8.3%): one HBeAg-positive and one HBeAg-negative patient. CONCLUSION: The outcomes of sequential therapy involving an early switch from entecavir to PegIFNα-2a were unsatisfactory in Japanese patients with CHB. In addition to viral factors, host metabolic characteristics and liver fibrosis/tumor markers can be used for prediction of a sustained response to therapy, but accurate prediction of the therapeutic response is difficult.

M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics.

Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγ(null) mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12(+)IL-10(-)CD163(-)CD14(+) cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1(+)CD163(+)CD14(+) cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12(-)IL-10(-)CCL1(-)CD163(-)CD14(+) cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes.

The preventive effect of the impaired liver function for antiemetic therapy against chemotherapy-induced nausea and vomiting in hepatocellular carcinoma patients.

Transarterial chemoembolization and hepatic arterial infusion chemotherapy are recommended for the treatment in patients with intermediate stage of hepatocellular carcinoma. Impaired liver function was sometime observed in patients with hepatocellular carcinoma after transarterial chemoembolization or hepatic arterial infusion chemotherapy. However, what kinds of factors deeply influence in impaired liver function are not clear. A retrospective study was performed to evaluate the risk factors of impaired liver function in cisplatin-naïve patients treated with these therapies using cisplatin. Prior to and 2 months after these therapies, we analyzed the liver function by Child-Pugh score in these patients. For assessing the severity of chemotherapy-induced nausea and vomiting, we utilized the Common Terminology Criteria for Adverse Events ver. 4.0. In hepatocellular carcinoma patients received these therapies using cisplatin, the cancer stage and treatment without neurokinin-1 (NK1) antagonist were found to be independent risk factors of the impaired liver function. The treatment with NK1 antagonist was effective in reducing chemotherapy-induced nausea and vomiting and patients treated with NK1 antagonist kept their liver functions after cisplatin-used these therapies. The treatment with NK1 antagonist was effective in chemotherapy-induced nausea and vomiting and prevented the impaired liver function associated with cisplatin-used these therapies in hepatocellular carcinoma patients.

Gene expression and localization analysis of Bombyx mori bidensovirus and its putative receptor in B. mori midgut.

Bombyx mori bidensovirus (BmBDV), which causes fatal flacherie disease in the silkworm, replicates only in midgut columnar cells. The viral resistance expressed by some silkworm strains, which is characterized as non-susceptibility irrespective of the viral dose, is determined by a single gene, nsd-2. We previously identified nsd-2 by positional cloning and found that this gene encodes a putative amino acid transporter that might function as a receptor for BmBDV. In this study, we investigated the relationship between the part of the midgut expressing nsd-2 (resistance gene), +(nsd-2) (susceptibility gene) and BmBDV propagation. Quantitative RT-PCR (qRT-PCR) analysis using total RNA isolated from the anterior, middle, and posterior parts of the midgut showed that nsd-2 and +(nsd-2) were strongly expressed in the posterior part of the midgut. The expression levels of both genes were very low in the anterior and middle parts. The qRT-PCR analysis showed that the expression levels of BmBDV-derived transcripts were correlated with the levels of +(nsd-2) expression. However, BmBDV-derived transcripts were clearly detected in all parts of the midgut. These results suggest that the infectivity of BmBDV depends mainly on the expression level of +(nsd-2) in the midgut and that viral infection is supported even by very faint expression of +(nsd-2). By contrast, the expression levels of +(nsd-2) were exceedingly low or undetectable in the middle part of the midgut, indicating that BmBDV infection might occur via another mechanism, independent of +(nsd-2), in the middle part of the midgut.

Effects of Oral L-Carnitine on Liver Functions after Transarterial Chemoembolization in Intermediate-Stage HCC Patients.

Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions. Methods. 53 cirrhotic hepatocellular carcinoma patients at Osaka Medical College were enrolled in this study and assigned into either L-carnitine group receiving 600 mg oral L-carnitine daily or control group. Liver functions were evaluated at pre-TACE and 1, 4, and 12 weeks after TACE. Results. The L-carnitine group maintained Child-Pugh (CP) score at 1 week after TACE and exhibited significant improvement at 4 weeks after TACE (P < 0.01). Conversely, the control group reported a significant CP score deterioration at 1 week (P < 0.05) and 12 weeks after TACE (P < 0.05). L-carnitine suppressed serum albumin deterioration at 1 week after TACE. There were significant differences between L-carnitine and control groups regarding mean serum albumin changes from baseline to 1 week (P < 0.05) and 4 weeks after TACE (P < 0.05). L-carnitine caused prothrombin time improvement from baseline to 1, 4 (P < 0.05), and 12 weeks after TACE. Total bilirubin mean changes from baseline to 1 week after TACE exhibited significant differences between L-carnitine and control groups (P < 0.05). The hepatoprotective effects of L-carnitine were enhanced by branched chain amino acids combination. Conclusion. L-carnitine maintained and improved liver functions after TACE.

Sitagliptin can inhibit the development of hepatic steatosis in high-fructose diet-fed ob/ob mice.

The beneficial effect of dipeptidyl peptidase-4 inhibition on diet-induced extra-pancreatic effects, especially on liver tissue remains poorly understood. Thus, we made the experimental designs as follows; five-week-old male ob/ob mice, which develop type 2 diabetic mellitus and nonalcoholic fatty liver disease by taking a high-carbohydrate diet (HCD), were divided into a group in which a HCD was given for 8 weeks as control, and another in which a HCD added with 0.0018% sitagliptin was given for 8 weeks. Hepatic steatosis was seen in all mice, but the mean grade of steatosis in the sitagliptin-administrated mice was significantly decreased. The acetyl-CoA concentrations were lower in sitagliptin-administrated mice, although the differences were not significant. However, the malonyl-CoA concentrations were significantly lower in sitagliptin-administrated mice. The expression of acetyl-CoA carboxylase 1 was inhibited in sitagliptin-administrated mice, irrespective of expressions of carbohydrate responsive element-binding protein (ChREBP) or sterol regulatory element-binding protein (SREBP)-1c. In conclusion, sitagliptin may affect the development of nonalcoholic fatty liver disease by inhibiting the production of malonyl-CoA and thus synthesis of fatty acids in the liver.

Safety and efficacy of faldaprevir with pegylated interferon alfa-2a and ribavirin in Japanese patients with chronic genotype-1 hepatitis C infection.

BACKGROUND & AIMS: Faldaprevir (BI 201335) is a potent once-daily (QD) NS3/4A protease inhibitor for the treatment of patients with genotype-1 (GT-1) hepatitis C virus (HCV). The aim of this study was to evaluate the safety, pharmacokinetics and efficacy of faldaprevir plus pegylated interferon alfa-2a (PegIFN) and ribavirin (RBV) in Japanese patients infected with chronic GT-1 HCV. METHODS: Part 1 of this phase II study was a randomized, double-blind, placebo-controlled, dose-ascending study. Treatment-naïve patients received faldaprevir 120 or 240 mg QD, or placebo, plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. In Part 2 (open label), treatment-experienced patients received faldaprevir 240 mg QD plus PegIFN/RBV for 4 weeks, then PegIFN/RBV alone for 44 weeks. Efficacy was assessed using sustained virological response (SVR) 24 weeks after treatment completion. The pharmacokinetics, safety and tolerability of faldaprevir were also assessed. RESULTS: SVR was achieved by 4/6 (67%) treatment-naïve patients treated with faldaprevir 120 mg QD, 5/6 (83%) patients treated with faldaprevir 240 mg QD and 2/4 (50%) patients who received placebo. Of the treatment-experienced patients, 3/6 (50%) achieved SVR. Faldaprevir was well tolerated. There was one serious adverse event, which was not considered to be treatment related. Rash and hyperbilirubinaemia were more frequently reported with faldaprevir than with placebo in treatment-naïve patients, but no cases were severe or serious and none led to discontinuation. Steady-state plasma concentrations of faldaprevir were reached within 7 days of QD dosing. CONCLUSIONS: Faldaprevir with PegIFN/RBV was efficacious and well tolerated, supporting further evaluation of this combination in Japanese patients.

Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats.

Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.

Is administrating branched-chain amino acid-enriched nutrition achieved symptom-free in malnourished cirrhotic patients?

Administration of branched-chain amino acids (BCAA) has been reported to improve liver function, quality of life (QOL). However, in some malnourished patients, serum albumin levels do not improve in response to BCAA granules. In this study, we examined the effects of BCAA-enriched enteral nutrition in patients unresponsive to BCAA granules. Thirty-two decompensated cirrhotic patients at Osaka Medical College were enrolled in this study. Since all patients showed no improvement in serum albumin levels despite 3 months of BCAA granule administration, they were administered 50 g of a flavored BCAA-enriched enteral nutrient twice daily, i.e., during the daytime and late evening. Serum albumin levels and major cirrhotic symptoms were examined 1, 3, and 5 months after treatment initiation. Serum albumin levels improved significantly 3 months after treatment initiation (3.14 ± 0.32 g/dl vs 3.5 ± 0.31 g/dl, p<0.01), and Child-Pugh scores decreased significantly (p<0.01). In the majority (53-80%) of patients, muscles cramps, fatigue, fatigability, edema, and sleep disturbance improved within 3 months after therapy initiation. Moreover, approximately 90% of the patients became symptom-free 5 months after treatment initiation. These results indicate that switching to BCAA-enriched nutrients improves QOL of cirrhotic patients unresponsive to BCAA granules.

Serum zinc value in patients with hepatitis virus-related chronic liver disease: association with the histological degree of liver fibrosis and with the severity of varices in compensated cirrhosis.

The relationships between the serum mineral concentrations and the endoscopic findings of esophageal varices have been poorly investigated. In this study, we investigated hepatitis virus-positive patients who had undergone a liver biopsy (n = 576) and 75 patients with compensated cirrhosis in order to evaluate the association of the zinc value with the severity of liver fibrosis and esophageal varices. The mean zinc values decreased with the progression of fibrosis (METAVIR score; F0-1: 71.3 ± 11.3, F2: 68.9 ± 11.7, F3: 66.3 ± 11.8, F4: 63.9 ± 15.0). In the hepatitis virus-related compensated cirrhosis, the mean zinc value decreased with the severity of varices (patients without varices: 66.3 ± 12.6, patients with low-risk varices: 62.5 ± 13.7, patients with high-risk varices: 55.6 ± 13.0). The zinc value was significantly lower in patients with varices than in those without varices (59.3 ± 13.6 vs 66.3 ± 12.6, p<0.05). The zinc value was also significantly lower in the patients with a high risk of bleeding than in those with a low risk (55.6 ± 13.0 vs 64.6 ± 13.1, p<0.01). These findings suggest that the zinc value is not only an indicator of an abnormal metal metabolism, but is also a simple parameter associated with hepatitis virus-related various conditions, including the degree of liver fibrosis and the severity of esophageal varices in compensated cirrhosis.

Elucidating nonlinear pharmacokinetics of telmisartan: Integration of target-mediated drug disposition and OATP1B3-mediated hepatic uptake in a physiologically based model.

Telmisartan, a selective inhibitor of angiotensin II receptor type 1 (AT1), demonstrates nonlinear pharmacokinetics (PK) when orally administered in ascending doses to healthy volunteers, but the underlying mechanisms remain unclear. This study presents a physiologically based pharmacokinetic model integrated with target-mediated drug disposition (TMDD-PBPK model) to explore the mechanism of its nonlinear PK. We employed the Cluster-Gauss Newton method for top-down analysis, estimating the in vivo Km,OATP1B3 (Michaelis-Menten constant for telmisartan hepatic uptake via Organic Anion Transporting Polypeptide 1B3) to be 2.0-5.7 nM. This range is significantly lower than the reported in vitro value of 810 nM, obtained in 0.3% human serum albumin (HSA) conditions. Further validation was achieved through in vitro assessment in plated human hepatocytes with 4.5% HSA, showing a Km of 4.5 nM. These results underscore the importance of albumin-mediated uptake effect for the hepatic uptake of telmisartan. Our TMDD-PBPK model, developed through a "middle-out" approach, underwent sensitivity analysis to identify key factors in the nonlinear PK of telmisartan. We found that the nonlinearity in the area under the concentration-time curve (AUC) and/or maximum concentration (Cmax) of telmisartan is sensitive to Km,OATP1B3 across all dosages. Additionally, the dissociation constant (Kd) for telmisartan binding to the AT1 receptor, along with its receptor abundance, notably influences PK at lower doses (below 20 mg). In conclusion, the nonlinear PK of telmisartan appears primarily driven by hepatic uptake saturation across all dose ranges and by AT1-receptor binding saturation, notably at lower doses.

Awareness of cancer and its associated factors for parents of adolescents and young adults: A cross-sectional study.

Cancer is a common health problem worldwide. Early cancer education for adolescents and young adults (AYAs) is important for the prevention or early detection of cancer. In this questionnaire-based cross-sectional study, we examined the cancer awareness among parents of AYAs. Japanese adults with junior or senior high school children were included in this study. The cancer awareness measure (CAM) was used to assess cancer awareness, and the survey was conducted in December 2021. Warning signs, barriers to seeking help, and risk factors were surveyed using an online anonymous questionnaire. In addition, personal information, the presence of other cancer survivors, attendance at cancer seminars, conversations with children about cancer, interest in cancer education for children, and previous cancer screening were surveyed. A t-test or Spearman correlation coefficient was used to compare the total CAM scores for the individual factors. The relationship between cancer-screening behavior and individual factors was analyzed using the χ2 test. In addition, multiple regression analysis or logistic regression analysis was used to identify the factors influencing cancer awareness or cancer-screening behavior. Responses were obtained from the 612 participants. The mean CAM score was 3.7 for cancer warning signs, 4.3 for barriers to seeking help, and 6.5 for risk factors. Cancer warning signs were associated with gender and the presence of a spouse, family member, or friend who had experienced cancer. Barriers to seeking help were associated with age, gender, and education, while risk factors were associated with gender, education, and conversations about cancer with children. Moreover, these scores were associated with each cancer screening behavior. Cancer awareness among Japanese adults with AYAs was influenced by gender, academic background, occupation, the presence of cancer survivors around them, and whether they had conversations about cancer with their children, as well as their cancer screening behavior.

Cancer awareness and its related factors among junior high and high school teachers in Japan: a cross-sectional survey.

BACKGROUND: The early detection and prevention of many cancers is possible. Therefore, public awareness about cancer risk factors and warning signs must be increased to ensure early diagnosis. Although Japan has implemented mandatory cancer education in junior high and high schools, few studies have evaluated teachers' cancer awareness. This study aimed to determine Japanese junior high and high school teachers' awareness of cancer and related factors. METHODS: This cross-sectional study obtained data through an online questionnaire survey using questions from the Cancer Awareness Measure (CAM) developed by Cancer Research UK. Thirty items were selected from three CAM modules: cancer risk factors, cancer warning signs, and barriers to seeking help. Descriptive statistics were used for socio-demografic data and CAM module questions. The χ2 test was performed on the relationship between cancer awareness and socio-demographic data. Multiple logistic regression analysis was used to identify factors influencing cancer awareness. RESULTS: Respondents included 316 junior high school and 463 high school teachers (541 men; 238 women; average age = 48.2 years; average teaching experience = 23.5 years). An average of 5.41 out of 11 cancer risk factors were recognized. More than 70% of teachers recognized smoking, exposure to another person's cigarette smoke, and having a close relative with cancer as risk factors. On average, 4.52 out of 9 cancer warning signs were recognized. More than 50% of teachers recognized the warning signs of unexplained lump or swelling, unexplained weight loss, and unexplained bleeding. Barriers to seeking help had a low average score of 4.51 out of 20. However, the most commonly recognized "barriers to seeking help" were "too busy to make time," "difficult to make an appointment," "worried about what the doctor might find," and "too scared." Moreover, the common factors that affected awareness of cancer risk factors and cancer warning signs were gender and cancer experience of relatives. Factors that affected awareness of "barriers to seeking help" were "participation in cancer-related workshops," age, gender, and cancer experience of relatives. CONCLUSIONS: Cancer awareness education should consider interventions that can improve knowledge of the symptoms and signs related to cancer without increasing the awareness of barriers to seeking help.

Population pharmacokinetic/pharmacodynamic analysis of the DPP-4 inhibitor linagliptin in Japanese patients with type 2 diabetes mellitus.

OBJECTIVES: Linagliptin is a novel, highly selective and long acting DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Linagliptin exhibits non-linear pharmacokinetics (PK) due to saturable binding to plasma and tissue DPP-4. The aim of this study was to characterize the PK and PK/DPP-4 inhibition relationship of linagliptin in Japanese patients with T2DM using a population PK/DPP-4 model and to support the rationale for the therapeutic dose in Japanese patients by simulation. METHODS: Linagliptin plasma concentration and DPP-4 inhibition measurements from a placebo-controlled, parallel group multiple (28 days) dose trial that included 36 T2DM patients (18 patients each in 2.5 mg and 10 mg dose group) were used for analysis. Modeling was performed using FOCE INTERACTION estimation method implemented in NONMEM V. The linagliptin plasma concentration- and DPP-4 inhibition- time profiles were simulated for Japanese patients receiving 5 mg linagliptin once daily by the model established. RESULTS: Nonlinear PK of linagliptin in T2DM patients were well described by a 2-compartment model assuming concentration-dependent binding to DPP-4 in the central and peripheral compartment. Plasma DPP-4 inhibition was integrated in the model by relating the model-predicted DPP-4 occupancy with linagliptin linearly to DPP-4 inhibition. The simulation predicted that for the 5 mg dose group the trough DPP-4 inhibition at steady-state was 84.2%, which is higher than the target inhibition (≥80%) for an effective dose of DPP-4 inhibitor. In 2.5 mg dose group, steady-state DPP-4 inhibition of >80% was not maintained over 24 hours (observed and simulated). CONCLUSIONS: The nonlinear PK of linagliptin and its plasma DPP-4 inhibition in patients were well characterized by a target-mediated drug disposition model relating DPP-4 occupancy with linagliptin to DPP-4 inhibition. Simulations of plasma DPP-4 inhibition suggest that 5 mg linagliptin once daily is an appropriate therapeutic dose for Japanese patients with T2DM.

Impact of P-glycoprotein on intracellular drug concentration in peripheral blood mononuclear cells and K562 cells.

P-glycoprotein (P-gp) expression in lymphocytes is variable and 2-fold higher in rheumatoid arthritis (RA) patients with treatment resistance than in healthy subjects. To date the information on P-gp-mediated drug interaction in lymphocyte is limited. We analyzed the importance on P-gp in lymphocytes using peripheral blood mononuclear cells (PBMCs) together with K562, K562/Adr, and K562/Vin cells, which have various P-gp levels, as cell models, and dexamethasone, nintedanib and apafant as weak to good P-gp substrates. P-gp levels in K562, K562/Adr, and K562/Vin cells were 0.3-, 20-, and 106-fold of healthy PBMCs, respectively. While cell accumulation of apafant and nintedanib decreased in all cells with increasing P-gp levels, dexamethasone accumulation in K562/Adr was comparable to that in healthy PBMCs and K562 cells. Cell accumulations of substrates in cells with low P-gp expression were not significantly changed by the P-gp inhibitors at therapeutic concentrations. However, accumulation increased to 1.4-fold at highest in K562/Adr cells with higher P-gp expression than in PBMCs of the RA patients. These results suggest P-gp controls the cellular concentration of P-gp substrates in PBMCs or K562 cells but cellular concentration of a weak P-gp substrate would not be apparently affected even in cells with a sufficient P-gp expression.

Details of Cancer Education Programs for Adolescents and Young Adults and Their Effectiveness: A Scoping Review.

The purpose of this review was to establish what cancer education programs have been carried out aimed at adolescents and young adults (AYAs) and what outcomes they achieved. The databases used were MEDLINE, CINAHL, and Web of Science, and the search period was set as 2011-2020. The extracted literature was evaluated for quality using the Joanna Briggs Institute's critical appraisal tools. The subjects of the analysis were 29 studies: 10 randomized controlled trials and 19 quasi-experimental designs. Regarding the varieties of cancers found in the data, in descending order, 10 documents looked at cervical cancer, 9 looked at cancer in general, and 4 looked at breast cancer. Most studies focused on AYAs exclusively, with just three studies involving their parents simultaneously. Many studies used lecture-based intervention, with information technology-based interventions using websites and cell phones. Topics included in the program were cancer epidemiology, cancer risk factors, cancer warning signs and symptoms, prevention methods, and screening methods. After the intervention, all studies showed statistically significant improvements in at least one outcome measure, which included knowledge and awareness of cancer, health beliefs, and intent to take preventive action, demonstrating a basis for educational intervention. Educating AYAs about cancer at a time when their ways of life are becoming more concrete can be expected to have a positive impact on cancer preventing behaviors in adulthood, increase their parents' awareness of cancer, and have a positive impact on behavior around screening.

Provider-Documented Dyspnea in Intensive Care Unit After Lung Transplantation.

BACKGROUND: Dyspnea is an important problem that might affect the clinical course after lung transplantation; however, the prevalence, risk factors, and relevant outcomes of dyspnea in the intensive care unit (ICU) after lung transplantation remain unknown. METHODS: This retrospective, observational study enrolled consecutive patients aged ≥ 20 years who were admitted to the ICU after lung transplantation between January 2010 and December 2020. The main outcome measure was provider-documented dyspnea identified based on a comprehensive retrospective chart review to extract dyspnea episodes (e.g., documented words related to "dyspnea," "shortness of breath," or "breathlessness"). RESULTS: This study included 184 lung transplant recipients, including 115 bilateral (63%) and 69 single (37%) lung transplants. Fifty-four transplants were from living donors (29%), and 130 were from deceased donors (71%). Dyspnea was documented in 116 patients (63%). Multivariate analysis identified bilateral lung transplantation (odds ratio = 5.127; 95% confidence interval, 2.020-13.014; P < .001) as a risk factor for dyspnea. In addition, postoperative anxiety (odds ratio = 18.605; 95% confidence interval, 7.748-44.674; P < .001) was independently associated with dyspnea. Patients with documented dyspnea showed delayed rehabilitation (P < .001) and weaning from mechanical ventilation (P < .001) and a longer ICU stay (P < .001). CONCLUSION: This study demonstrated that the prevalence of dyspnea in the ICU after lung transplantation was frequent and identified bilateral lung transplantation as a risk factor. Dyspnea caused a delay in rehabilitation and weaning from mechanical ventilation. Extensive evaluation and care for dyspnea and anxiety may enhance patient recovery.

The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers.

OBJECTIVE: Telmisartan is mainly taken up into the liver by organic anion transporting polypeptide (OATP) 1B3, conjugated with glucuronate, and excreted into the bile. We investigated the relationship between genotypes of metabolizing enzymes and transporters and pharmacokinetics of telmisartan in clinical study. We also checked which enzymes are responsible for telmisartan glucuronidation. MATERIALS AND METHODS: We collected blood samples from 57 healthy volunteers who had participated in a clinical trial of telmisartan and examined the relationship between 14 mutations in six transporters/metabolic enzymes and pharmacokinetics of telmisartan. We also performed an in-vitro glucuronidation assay with recombinant uridine 5'-diphospho-glucuronosyltransferases isoforms and human liver microsomes. RESULTS: In the clinical study, area under the plasma concentration-time curve value from time zero to infinity, of telmisartan in heterozygotes of SLCO1B3 (encoding protein: OATP1B3) rs11045585 tended to be larger than that in homozygotes of wild-type alleles. Unexpectedly, 19 heterozygotes of UGT1A1*28, whose function was decreased, significantly increased its oral clearance compared with homozygotes of UGT1A1*1 alleles (1090±690 vs. 620±430 ml/min/body). Metabolic clearance of telmisartan in human liver microsomes obtained from individuals with UGT1A1*28/*28 was higher compared with that of UGT1A1*1/*1 (168±33 vs. 93.3±27.3 µl/min/mg protein). Although telmisartan was metabolized by multiple UGT isoforms, in-vitro experiments revealed that UGT1A3 was estimated to be predominantly involved in telmisartan glucuronidation in human hepatocytes. CONCLUSION: UGT1A1*28 was thought to enhance the protein expression of UGT1A3 as reported most recently (Riedmaier et al. Clin Pharmacol Ther 2010; 87:65-73) and thereby increase glucuronidation activity of telmisartan and decrease the plasma concentration of telmisartan.

Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tamsulosin metabolism involves both CYP2D6 and 3A4. However, data on potential drug-drug interactions between tamsulosin and inhibitors of CYP2D6 and 3A4 are limited and information on potential pharmacodynamic consequences of such pharmacokinetic interactions is missing. WHAT THIS STUDY ADDS: This study provides information on the drug-drug interactions of tamsulosin with strong CYP2D6 and strong CYP3A4 inhibitors after single dose administration in healthy subjects. AIM: To determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin. METHODS: Two open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers). RESULTS: Co-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C(max) and AUC(0,∞) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t(1/2) ) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once daily with a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C(max) and AUC(0,∞) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing. CONCLUSION: The exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing.