Prediction of drug-drug interaction risk of P-glycoprotein substrate in drug discovery.

We aimed at predicting the drug-drug interaction (DDI) risk of P-glycoprotein (P-gp) substrates by using P-gp expressing LLC-PK1 cells and its knockout mice (KO). The area under the curve (AUC) of 16 marketed drugs and plasma concentration (Cplasma) of 207 screening compounds, with corrected efflux ratio (CER) ≥ 2, were compared between P-gp KO mice and wild type mice (WT). At permeability (Papp) ≥ 10 × 10-6 cm/s in parent LLC-PK1 cells, AUC ratios (KO/WT) and Cplasma ratios (KO/WT) of these compounds were within 3-fold. AUC ratios (KO/WT) of clinical P-gp substrates, with human AUC ratios with and without P-gp inhibitor administration ≥2, were higher than 8.7. These observations led us to establish a work-flow of P-gp substrate assessment with the threshold AUC ratio (KO/WT) ≥ 9 leading to a DDI risk of AUC ratio (human) ≥ 2. A screening compound showing high CER (=57.6) was found, but its AUC ratio (KO/WT) was 3.7, had been presumed to be a weak risk and its AUC ratio (human) was 1.2 in a later clinical DDI study. Our proposed workflow should be useful for predicting the DDI risk of P-gp substrates in drug discovery.

Associations of ADH1B and ALDH2 genotypes and alcohol flushing with drinking history, withdrawal symptoms, and ICD-10 criteria in Japanese alcohol-dependent men.

OBJECTIVES: Given the high prevalence of fast-metabolizing alcohol dehydrogenase-1B*2 (ADH1B*2) and inactive aldehyde dehydrogenase-2*2 (ALDH2*2) alleles in East Asians, we evaluated how the ADH1B/ALDH2 genotypes and alcohol flushing might affect the development of alcohol dependence (AD). METHODS: We evaluated how the ADH1B/ALDH2 genotypes and self-reported alcohol flushing affected history of drinking events and withdrawal symptoms and ICD-10 criteria in 4116 Japanese AD men. RESULTS: The ADH1B*1/*1 group and ALDH2*1/*1 group were 1-5 years younger than the ADH1B*2(+) and ALDH2*1/*2 groups, respectively, for all of the ages at onset of habitual drinking, blackouts, daytime drinking, uncontrolled drinking, withdrawal symptoms, and first treatment for AD, and the current age. Blackouts were more common in the ADH1B*1/*1 group and ALDH2*1/*1 group. Daytime drinking, uncontrolled drinking, and withdrawal symptoms, such as hand tremor, sweating, convulsions, and delirium tremens/hallucinations were more common in the ADH1B*1/*1 group. The ADH1B*1/*1 was positively associated with the ICD-10 criteria for 'tolerance' and 'withdrawal symptoms'. The ADH1B*1/*1 group and ALDH2*1/*2 group had a larger ICD-10 score. Never flushing was reported by 91.7% and 35.2% of the ALDH2*1/*1 and ALDH2*1/*2 carriers, respectively. After a 1-2-year delay in the onset of habitual drinking in the former-/current-flushing group, no differences in the ages of the aforementioned drinking milestones were found according to the flushing status. CONCLUSION: The ADH1B*1/*1 and ALDH2*1/*1 accelerated the development of drinking events and withdrawal symptoms in Japanese AD patients. ICD-10 score was larger in the ADH1B*1/*1 group and ALDH2*1/*2 group. The effects of alcohol flushing on drinking events were limited.

Utility of Coproporphyrin-I Determination in First-in-Human Study for Early Evaluation of OATP1B Inhibitory Potential Based on Investigation of Ensitrelvir, an Oral SARS-CoV-2 3C-Like Protease Inhibitor.

Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals with ensitrelvir were reported during the study. CONCLUSION: The inhibitory effect for CYP3A was confirmed after the last dose of ensitrelvir, and the effect diminished over time. In addition, ensitrelvir at 375/125 mg showed CYP3A inhibitory potential similar to that at 750/250 mg. These findings can be used as a clinical recommendation for prescribing ensitrelvir with regard to concomitant medications. CLINICAL TRIAL REGISTRATION: Japan Registry of Clinical Trials identifier: jRCT2031210202.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates.

Increasing important roles of child and adolescent psychiatrists in the treatment of gaming disorder: Current status in Japan.

Background: Digital gaming is the most common leisure activity among children and adolescents in Japan, especially in males. Playing online gaming has become more common among school-age children over the years. As a result, excessive online gaming in younger children has become a significant social problem in Japan. Previous studies have demonstrated that excessive online gaming could cause various mental health issues in children and adolescents. At medical institutions having child and adolescent psychiatry services, there is an increasing number of children and adolescents with various problems related to excessive gaming. The aim of this study was to investigate the current practice of gaming disorder (GD) in clinical settings in Japan. Methods: The subjects of this study were all of 414 child and adolescent psychiatrists certified by the Japanese Society for Child and Adolescent Psychiatry (JSCAP). The study questionnaire was mailed to all subjects from the official secretariat of JSCAP. Study subjects were requested to answer the questionnaire anonymously. The survey contained three types of responses: open responses; single and multiple-choice responses; and, responses on a five-point Likert scale. The questionnaire consisted of 14 questions regarding GD. Results: We received 159 responses. The most common reason for a visit to child and adolescent psychiatry service which results in a subsequent diagnosis of GD was school refusal/absenteeism followed by disruption of sleep-awake rhythm. The most common specialized treatment for GD currently offered at child and adolescent psychiatry service is individual psychotherapy. The two most frequently experienced difficulties in the treatment of GD were low motivation to achieve recovery and a large variety of combined problems other than excessive gaming itself. With regard to the three most common psychiatric comorbidities of GD, they were autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and depression. Discussion: The results of our survey revealed that although GD is a behavioral addiction, many children and adolescents with GD first visit child and adolescent psychiatry clinics rather than specialized clinics for addiction which are usually designed and staffed for adult patients. Because it is known that GD is more prevalent among young males, including junior high and high school students, GD has become one of the most important clinical issues in child and adolescent psychiatry today. The important roles of child and adolescent psychiatrists in the treatment of GD has been increasing.

Validation of the Ten-Item Internet Gaming Disorder Test (IGDT-10) based on the clinical diagnosis of IGD in Japan.

Background and aims: Although the Ten-Item Internet Gaming Disorder Test (IGDT-10) has been translated into Japanese and widely used, the Japanese version has not previously been validated. We used the clinical diagnosis of IGD as a gold standard for validating the test. Methods: The Japanese version was validated using 244 gamers drawn from the general young population in Japan. Expert interviews using the Japanese version of the Structured Clinical Interview for Internet Gaming Disorder evaluated diagnoses of Internet gaming disorder (IGD). This resulted in a diagnosis of IGD for eight individuals, categorized as the gold standard group. The screening performance of the two Japanese versions with different scoring conditions was examined: the scoring method proposed by the original study (original version) and a less stringent scoring method where responses of either "often" or "sometimes" were regarded as affirmative (modified version). Results: The results of the sensitivity and specificity analyses, the Cronbach's alpha and the receiver operating characteristics analysis revealed a higher screening performance for the modified versus the original version. The optimum cutoff for the modified version was 5 or more - the sensitivity, specificity, and Youden's index were 87.5, 85.2, and 72.7%, respectively. The rate of probable IGD using the original and modified versions were 1.8% and 11.3%, respectively. Discussion and conclusion: A less stringent scoring method for the Japanese version of IGDT-10 showed a higher screening performance than the original scoring method. Future studies comprising different ethnic groups and gaming cultures should further examine the suggested scoring method.

Species difference in brain penetration of P-gp and BCRP substrates among monkey, dog and mouse.

The brain penetration of 19 drugs, including P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) substrates, was compared among mice, cynomolgus monkeys and beagle dogs. The brain-to-plasma concentration ratios (Kp,brain) of the tested compounds in monkey and dog showed good correlation, whereas species differences were observed between non-rodents (monkey/dog) and rodents (mouse). In particular, the Kp,brain values of 7 compounds out of 12 P-gp substrates (Kp,brain ratio in P-gp knockout mice versus wild-type mice ≥3) in monkey and dog were more than three-fold higher than those in mice and a similar trend was observed in the brain-to-plasma unbound concentration ratios (Kp,uu,brain). The cerebral spinal fluid (CSF) drug concentrations (CCSF), a surrogate for unbound brain concentration (Cu,brain), were also compared between dog and monkey, and the CSF-to-plasma unbound concentration ratios (Kp,uu,CSF) of BCRP substrates in dog were notably higher than those in monkey, although non-bcrp substrates showed good correlation. Also, the Kp,uu,CSF values of BCRP substrates in dog were clearly higher than the Kp,uu,brain values, indicating that the dog CCSF of BCRP substrates was not suitable as a surrogate of Cu,brain. These observations should be useful when selecting the appropriate animal models for CNS drug discovery.

Change of Internet Use and Bedtime among Junior High School Students after Long-Term School Closure Due to the Coronavirus Disease 2019 Pandemic.

Most schools in Japan were closed in spring 2020 due to the novel coronavirus disease 2019 (COVID-19) pandemic. We investigated lifestyle and internet use among junior high school students across eight schools after long-term school closure and compared the data with those we obtained from previous surveys. In the summers of 2018, 2019, and 2020, we conducted questionnaire surveys on seventh-grade students from the same schools. In total, 2270 participants were analyzed. All questionnaires included items regarding background, bedtime, and internet use. The participants of the 2020 survey had significantly less sleepiness during classes and longer internet use times compared with those of the previous surveys. In the 2020 survey, the rate of problematic internet use (Young's Diagnostic Questionnaire score, ≥5) was not significantly different from the results of previous surveys. The COVID-19 pandemic might have strongly influenced the sleepiness experienced by students in classes and increased the time spent using the internet since the summer of 2020. Our results indicate the need for attempts to encourage students to improve their sleep habits and moderate their media use.

Development and validation of a nine-item short screening test for ICD-11 gaming disorder (GAMES test) and estimation of the prevalence in the general young population.

BACKGROUND AND AIMS: A definition of gaming disorder (GD) was introduced in ICD-11. The purpose of this study was to develop a short screening test for GD, utilizing a reference GD group. It also sought to estimate the prevalence of GD among individuals, representative of the general young population in Japan. METHODS: Two hundred eighty one men and women selected from the general population, aged between 10 and 29 years, and 44 treatment seekers at our center completed a self-reported questionnaire comprising candidate questions for the screening test. The reference group with ICD-11 GD was established, based on face-to-face interviews with behavioral addiction experts, using a diagnostic interview instrument. The questions in the screening test were selected to best differentiate those who had GD from those who did not, and the cutoff value was determined using the Youden index. RESULTS: A nine-item screening test (GAMES test) was developed. The sensitivity and specificity of the test were both 98% and the positive predictive value in the study sample was 91%. The GAMES test comprised two factors, showed high internal consistency and was highly reproducible. The estimated prevalence of GD among the general young population was 7.6% (95% confidence interval; 6.6-8.7%) for males and 2.5% (1.9-3.2%) for females, with a combined prevalence of 5.1% (4.5-5.8%). DISCUSSION AND CONCLUSION: The GAMES test shows high validity and reliability for screening of ICD-11 GD. The estimated prevalence of 5.1% among the general young population was comparable to the pooled estimates of young people globally.

Application of the eleventh revision of the International Classification of Diseases gaming disorder criteria to treatment-seeking patients: Comparison with the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders Internet gaming disorder criteria.

BACKGROUND AND AIMS: The World Health Organization included gaming disorder (GD) in the eleventh revision of International Classification of Diseases in 2019. Due to the lack of diagnostic tools for GD, a definition has not been adequately applied. Therefore, this study aimed to apply an operationalized definition of GD to treatment-seekers. The relationship between the diagnoses of GD and Internet gaming disorder (IGD) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders was also examined. Methods: Study participants comprised 241 treatment-seekers who had engaged in excessive gaming and experienced related problems. Psychiatrists applied the GD diagnostic criteria to the participants using a diagnostic form developed for this study. Information on gaming behavior and functional impairment was obtained through face-to-face interviews conducted by clinical psychologists. Results: In total, 78.4 and 83.0% of the participants fulfilled the GD and IGD diagnostic criteria, respectively. The sensitivity and specificity of GD diagnosis were both high when the IGD diagnosis was used as the gold standard. Participants with GD preferred online PC and console games, spent significantly more time gaming, and showed a higher level of functional impairment compared to those who did not fulfill the GD diagnostic criteria. Discussion and Conclusion: The definition of GD can be successfully applied to treatment-seekers with excessive gaming and related problems. A high concordance of GD and IGD diagnoses was found in those participants with relatively severe symptoms. The development and validation of a diagnostic tool for GD should be explored in future studies.

Preventive effects of naldemedine, peripherally acting µ-opioid receptor antagonist, on morphine-induced nausea and vomiting in ferrets.

AIMS: Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORAs) indicated for the treatment of opioid-induced constipation (OIC). We investigated the preventive effect of naldemedine on morphine-induced nausea and vomiting in ferrets and conducted a pharmacokinetic/pharmacodynamic (PK/PD) analysis. MAIN METHODS: The antiemetic effect of naldemedine was evaluated as the frequency and time of retching (rhythmic abdominal contractile motion) and vomiting (throwing up vomit or similar reactions) caused by morphine in ferrets. After a single oral administration of naldemedine to ferrets, the plasma concentrations of naldemedine and morphine were measured by liquid chromatography-tandem mass spectrometry. KEY FINDINGS: Naldemedine showed a potent and dose-dependent anti-emetic effects against morphine-induced emetic responses, for up to 6 h. The dose of naldemedine that produced half the maximal effect (ED50) value for anti-emetic effect of naldemedine in the morphine-treated ferrets was 0.033 mg/kg. The PK/PD analysis revealed that the antiemetic effect was related to the plasma naldemedine concentration, with a half maximal effective concentration that produces half the maximal effect (EC50) of 3.51 ng/mL. The plasma concentration producing an antiemetic effect was almost 200-fold lower than that inducing an anti-analgesic effect in rats. SIGNIFICANCE: Naldemedine showed potent inhibition of morphine-induced vomiting for up to 6 h after dosing. These data suggest that naldemedine possesses antiemetic properties and could be effective against opioid-induced nausea and vomiting (OINV).

The antagonistic activity profile of naloxone in µ-opioid receptor agonist-induced psychological dependence.

Naloxone is a µ-opioid receptor antagonist that has been used to prevent overdose-related respiratory depression and deaths by the illicit use of opioids. Naloxone can also deter the abuse potential of opioids, but little has been reported regarding its antagonistic activity profile against opioid-induced psychological dependence. This study aimed to confirm the antagonistic activity profile of naloxone against several µ-opioid receptor agonists and investigate whether naloxone could affect the psychological dependence induced by widely used µ-opioid receptor agonist, oxycodone. In the Guanosine-5'-o-(3-thio) triphosphate (GTPγS) binding assay, naloxone (30-30,000 nM) inhibited the GTPγS binding induced by oxycodone, hydrocodone, morphine, and fentanyl. It elicited parallel rightward shifts in the concentration-response curves, indicating that naloxone possessed a competitive antagonistic activity profile against these µ-opioid receptor agonists. In the conditioned place preference test, oxycodone (0.01-1 mg/kg, i.v.) produced dose-dependent increases in place preference. The increased place preference induced by oxycodone (1 mg/kg) was significantly attenuated by co-administration of naloxone at a dose of 0.5 mg/kg but not 0.01 mg/kg. Naloxone (0.5 mg/kg, i.v.) also blocked oxycodone (1 mg/kg)-induced dopamine release in nucleus accumbens; however, at a lower dose (0.01 mg/kg), it did not affect the intrinsic dopamine release by oxycodone. These results indicate that the psychological dependence of oxycodone could be antagonized by naloxone, depending on the dose. This characterization might lead to a better understanding of the competitive antagonistic activity profile of naloxone for µ-opioid receptor in the brain.

The antiviral effects of baloxavir marboxil against influenza A virus infection in ferrets.

BACKGROUND: Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients. OBJECTIVES: To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets. METHODS: Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM. RESULTS: The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4. CONCLUSIONS: The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.

Relationship between problematic gaming and age at the onset of habitual gaming.

BACKGROUND: Some studies have revealed that a substantial proportion of the younger population has engaged in problematic gaming with even infants recently being able to enjoy video games. However, the relationship between the risk for problematic gaming and age at which habitual gaming starts remains unknown. This study therefore investigated this relationship among adolescents. METHODS: A survey was conducted at eight public junior high schools across Japan. The questionnaire included items regarding the background, night-time sleep, age at which weekly gaming began, time spent on the Internet and gaming, the Japanese version of Young's Diagnostic Questionnaire, the Ten-Item Internet Gaming Disorder Test (IGDT-10), and others. We analyzed 549 participants who engaged in weekly gaming and have played games during the past year. RESULTS: Among the participants, 1.8% were suspected to have Internet gaming disorder (IGDT-10 ≥ 5). Bedtime and wake-up time on weekdays and holidays were significantly later among problematic gamers (IGDT-10 ≥ 3) than among normal gamers (IGDT-10 ≤ 2). Onset of weekly gaming before the age of 5 was associated with a significantly higher risk of problematic gaming than onset of weekly gaming after the age of 10. CONCLUSIONS: Our results revealed that the risk for problematic gaming was positively associated with a younger age at which weekly gaming begins. Longitudinal problematic gaming prevention, starting from an early stage, is thus necessary.

Unguided Chatbot-Delivered Cognitive Behavioural Intervention for Problem Gamblers Through Messaging App: A Randomised Controlled Trial.

Internet-delivered intervention may be an acceptable alternative for the more than 90% of problem gamblers who are reluctant to seek face-to-face support. Thus, we aimed to (1) develop a low-dropout unguided intervention named GAMBOT integrated with a messaging app; and (2) investigate its effect. The present study was a randomised, quadruple-blind, controlled trial. We set pre-to-post change in the Problem Gambling Severity Index (PGSI) as the primary outcome and pre-to-post change in the Gambling Symptom Assessment Scale (G-SAS) as a secondary outcome. Daily monitoring, personalised feedback, and private messages based on cognitive behavioural theory were offered to participants in the intervention group through a messaging app for 28 days (GAMBOT). Participants in the control group received biweekly messages only for assessments for 28 days (assessments only). A total of 197 problem gamblers were included in the primary analysis. We failed to demonstrate a significant between-group difference in the primary outcome (PGSI - 1.14, 95% CI - 2.75 to 0.47, p = 0.162) but in the secondary outcome (G-SAS - 3.14, 95% CI - 0.24 to - 6.04, p = 0.03). Only 6.7% of the participants dropped out during follow-up and 77% of the GAMBOT group participants (74/96) continued to participate in the intervention throughout the 28-day period. Integrating intervention into a chatbot feature on a frequently used messaging app shows promise in helping to overcome the high dropout rate of unguided internet-delivered interventions. More effective and sophisticated contents delivered by a chatbot should be sought to engage over 90% of problem gamblers who are reluctant to seek face-to-face support.

Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance.

In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule; however, the ability of these models to capture quantitatively the impact of perturbed conditions (e.g., urine flow, urine pH changes) on CLR has not been fully evaluated. In this work, we aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro human epithelial cell line Caco-2 permeability data by nephron tubular surface area to predict the fraction reabsorbed and the CLR of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole, and theophylline. CLR values predicted using mechanistic kidney model at a urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87- and 3.62-fold, respectively. Model simulations captured urine flow-dependent CLR, albeit with minor underprediction of the observed magnitude of change. The relationship between drug solubility, urine flow, and urine pH, illustrated in simulated intratubular concentrations of acyclovir and sulfamethoxazole, agreed with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CLR and drug tubular concentrations with the aim of facilitating refinement of IVIVE-based mechanistic prediction of renal excretion.

Improved Human Pharmacokinetic Prediction of Hepatically Metabolized Drugs With Species-Specific Systemic Clearance.

Accurate prediction of human pharmacokinetics (PK) is important for the choice of promising compounds in humans. As the predictability of human PK by an empirical approach is low for drugs with species-specific PK, the utility of a physiologically based pharmacokinetic (PBPK) model was verified using 16 hepatically metabolized reference drugs. After the prediction method for total clearance (CLtot) and distribution volume at steady state (Vdss) in the conventional PBPK model had been optimized, plasma concentrations following a single oral administration of each reference drug to healthy volunteers were simulated, and the prediction accuracy for human PK was compared between empirical approaches and the optimized PBPK model. In the drugs with low species-specific CLtot, there was little difference in predictability for maximum concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the curve (AUC) (absolute average fold error: 1.3-2.4). In contrast, the optimized PBPK model predicted Cmax and AUC of the drugs with high species-specific CLtot with lower absolute average fold error (Cmax and AUC: 2.8 and 3.2, respectively) than those of the empirical approach (Cmax and AUC: 2.6-4.9 and 3.9-10.7, respectively). Therefore, the optimized PBPK model is useful for human PK prediction of drugs with species-specific CLtot.

Effects of atrial natriuretic peptide on bicarbonate transport in long- and short-looped medullary thick ascending limbs of rats.

Atrial natriuretic peptide (ANP) is known to influence NaCl transport in the medullary thick ascending limbs (MAL), where the largest NaCl reabsorption occurs among distal nephron segments in response to arginine vasopressin (AVP). In the present study, we investigated the effect of ANP on bicarbonate (HCO3 (-)) transport in the MAL using an isolated tubule perfusion technique. The HCO3 (-) concentration was measured using free-flow ultramicro-fluorometer. We first observed basal HCO3 (-) reabsorption in both long- and short-looped MALs (lMALs, and sMALs, respectively). AVP inhibited HCO3 (-) reabsorption in both lMALs and sMALs, whereas ANP did not change HCO3 (-) transport. However, in the presence of AVP, ANP restored the HCO3 (-) reabsorption inhibited by AVP both in lMAL and sMAL. The effects of ANP on HCO3 (-) transport was mimicked by cyclic GMP. The mRNA expression level of the vasopressin V2 receptor in lMALs was significantly higher than in sMALs, whereas expression of the V1a receptor was unchanged. In summary, AVP inhibits HCO3 (-) transport, and ANP counteracts the action of AVP on HCO3 (-) transport both in lMALs and sMALs.