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Aims/Introduction Ultra‐rapid lispro (URLi) is a novel ultra‐rapid mealtime insulin. This study compared the pharmacokinetic and glucodynamic profiles, safety, and tolerability of URLi and lispro (Humalog®) in Japanese patients with type 1 diabetes mellitus. Materials and Methods This was a phase I, single center, randomized, patient‐ and investigator‐blind, two‐period, cross‐over study. A total of 31 patients received a single subcutaneous 15‐U dose of URLi or lispro before undergoing a euglycemic clamp procedure. Primary pharmacokinetic endpoints were the time to early half‐maximal drug concentration and the area under the concentration versus time curve from 0 to 30 min postdose. The glucodynamic endpoints were the time to early half‐maximal glucose infusion rate before time to maximum glucose infusion rate, and the time to onset of insulin action. Results URLi showed accelerated insulin lispro absorption compared with lispro, as shown by a decrease of 56% (URLi: 10.2 min, lispro: 23.3 min; P < 0.0001) in the early half‐maximal drug concentration, and a 2.4‐fold increase in the area under the concentration versus time curve from 0 to 30 min (P < 0.0001). The duration of insulin lispro exposure was 88 min shorter after URLi administration compared with lispro. URLi reduced the early half‐maximal glucose infusion rate before time to maximum glucose infusion rate and the time to onset of insulin action significantly compared with lispro. The glucose infused within the first 30 min of the clamp was 2.16‐fold greater with URLi compared with lispro. There was no difference in total exposure or glucose infused between treatments. All treatment‐emergent adverse events were mild/moderate in severity. Conclusions In Japanese type 1 diabetes mellitus patients, URLi showed accelerated insulin lispro absorption, reduced late exposure, overall shorter duration and faster early insulin action compared with lispro. Ultra‐rapid lispro is a novel ultra‐rapid mealtime insulin. This study compared the pharmacokinetic and glucodynamic profiles, safety, and tolerability of ultra‐rapid lispro and lispro (Humalog®) in Japanese patients with type 1 diabetes mellitus. Overall, ultra‐rapid lispro showed accelerated insulin lispro absorption, reduced late exposure, overall shorter duration and faster early insulin action compared with lispro in Japanese patients with type 1 diabetes mellitus.

In Japan, there is a registry for fertility treatment (the JSOG registry), which is a system that only registers select clinical data related to assisted reproductive technology (ART). This system does not include patient-derived data, so innovative tools that can complement the shortcomings of the existing registry may be useful. In this study we explored the potential of using a smartphone application platform to collect clinical data from patients directly. We recruited participants using the smartphone application “ Luna Luna ” and requested information that is typically gathered during a medical checkup, including basic physical characteristics, medical history, and results of fertility examinations such as hormone levels and semen analysis. We also asked the participants about the most recent fertility treatment they received and the details of the treatment. We recruited more than 13,000 participants within Japan nationwide in one month, and successfully collected information that is necessary in clinical practice for fertility treatment. Furthermore, through the participants, we were able to obtain information concerning their partners. We gained an expanded understanding of the circumstances surrounding fertility tests performed in Japan and details of fertility treatment such as ovarian stimulation and pregnancy outcomes by each fertility treatment method. This smartphone application has the potential as a promising tool for doctors and couples for information management during fertility treatment.

Purpose The current definition of menstrual cycle length in a Japanese woman is different from those of WHO definition, and the original data are outdated. We aimed to calculate the distribution of follicular and luteal phases length in modern Japanese women with various menstrual cycles. Methods This study determined the lengths of the follicular and luteal phases of Japanese women using basal body temperature data collected via a smartphone application from 2015 to 2019, and the data were analyzed using the Sensiplan method. Over 9 million temperature readings from more than 80 000 participants were analyzed. Results The mean duration of the low‐temperature (follicular) phase averaged 17.1 days and was shorter among participants aged 40–49 years. The mean duration of the high‐temperature (luteal) phase was 11.8 days. The variance and maximum‐minimum difference of the length of the low temperature period were significant in women under 35 years old than women aged more than 35 years. Conclusions The shortening of the follicular phase in women aged 40–49 years implied a relationship with the rapid decline of ovarian reserve in these women, and the age 35 years old was turning point of ovulatory function.

People of reproductive age have unmet needs related to deficiencies in fertility literacy. Here, we aimed to investigate whether providing fertility-related information via a smartphone application could improve fertility treatment-related literacy in participants. We performed a randomized control-group pretest posttest study and recruited participants between June 18 and 25, 2020. Participants’ fertility treatment-related literacy was assessed with a pretest that comprised of 28 questions and participants were allocated with stratified randomization to either intervention group or control group. The intervention comprised a one-week smartphone application-based provision of information on fertility-related information and the control group received general information about women’s healthcare. Effectiveness of intervention was assessed using a posttest. A total of 4137 participants were administered the questionnaire and pretest, among which 3765 participants (91.0 %) responded and were randomly allocated into either the intervention group ( N  = 1883) or the control group ( N  = 1882). A significantly higher posttest mean score was observed for the intervention group compared to the control group ( P  = 0.0017). We also observed that posttest scores were significantly improved compared to pretest scores in both the intervention and control group ( P  < 0.001). When examining by specific test question, the proportion answering correctly increased at posttest compared to pretest for both intervention and control groups ( P  < 0.001). Furthermore, the intervention group showed a greater mean difference between posttest and pretest scores than the control group ( P  < 0.001). In conclusion, educational intervention using a smartphone application contributed to enhancing fertility treatment-related literacy.

We aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of orforglipron in Japanese participants with type 2 diabetes. This was a double-blind, placebo-controlled, randomized, phase 1 study. In Part A, participants received single doses of orforglipron (2 or 3 mg) or placebo. In Part B, participants received multiple ascending doses of daily oral orforglipron (final target doses: 12, 24, and 45 mg) or placebo for 12 weeks. Parts A and B enrolled 23 and 60 participants, respectively. The most common treatment-emergent adverse events were gastrointestinal events of mild severity. No severe or serious adverse events were reported. At week 12, median t was 5.92-8.00 h, and mean terminal half-life was 51.8-76.1 h. Following multiple ascending doses, orforglipron groups had greater mean reductions from baseline to week 12 in glycemic parameters (fasting glucose: orforglipron 12 mg -64.8 mg/dL, 24 mg -61.1 mg/dL, 45 mg -65.6 mg/dL, placebo 7.4 mg/dL; glycated hemoglobin: orforglipron 12 mg -2.16%, 24 mg -2.17%, 45 mg -2.28%, placebo 0.67%) and body weight (orforglipron 12 mg -2.9 kg, 24 mg -6.3 kg, 45 mg -4.8 kg, placebo 0.3 kg) compared with placebo. In Japanese participants, safety, pharmacokinetic, and pharmacodynamic results were similar to those of previous orforglipron studies. The safety and tolerability of orforglipron were also consistent with those of other glucagon-like peptide-1 receptor agonists. Orforglipron is a potential new treatment option for Japanese patients with type 2 diabetes.

Introduction This analysis aimed to assess the safety and tolerability of insulin efsitora alfa (efsitora, basal insulin Fc, LY3209590) and characterize the pharmacokinetic and pharmacodynamic profiles of efsitora in Japanese patients with type 2 diabetes. Methods The single-dose escalation study assessed once-weekly efsitora administration in three patient cohorts: 5 mg for cohort 1; 10 mg for cohort 2 or placebo under double-blind conditions; and 20 mg for cohort 3 under open-label conditions. In the 6-week, multiple-dose study, patients started or continued using insulin degludec during the lead-in period, followed by randomization to efsitora (individualized fixed weekly dose) or insulin degludec (individualized fixed daily dose). Pharmacokinetics, pharmacodynamics, and safety were examined. Results The mean age was 58.3 and 58.4 years, and mean body mass index was 25.6 and 26.8 kg/m 2 in the single-dose escalation ( n  = 31) and multiple-dose studies ( n  = 28), respectively. The pharmacokinetic profile showed a prolonged half-life of 15 to 16 days, with a low peak-to-trough ratio of 1.13 after the last dose with little fluctuation. All doses of efsitora (5, 10, and 20 mg) decreased mean fasting glucose levels from baseline to day 15 (single-dose study), with no notable changes observed after switching from insulin degludec (multiple-dose study). All treatment-emergent adverse events were mild and unrelated to the study drug. No severe hypoglycemic events were reported. Conclusions Efsitora was well tolerated, and the pharmacokinetic and pharmacodynamic profiles were consistent with findings in prior global studies, supporting the participation of Japanese patients in phase 3 studies. Trial Registration ClinicalTrials.gov, NCT03603704; NCT04276428.

Background Nasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns. Objective The aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation. Methods We used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to < 8, 8 to < 12, and 12 to < 18 years. Treatment success was defined as an increase in blood glucose to ≥ 70 or ≥ 20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon. Results The data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that > 99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues. Conclusions This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.

Introduction Dulaglutide is a recombinant glucagon-like peptide-1 immunoglobulin G4 Fc fusion protein approved for treating patients with type 2 diabetes (T2D). The aim of this study was to assess postprandial data over 4 weeks for dulaglutide (0.75 mg) versus placebo after a standardized test meal in Japanese patients with T2D. Methods The pharmacodynamic (PD) effects of once-weekly dulaglutide (0.75 mg) in Japanese patients with T2D on diet and exercise therapy ( N  = 12) were evaluated by assessing postprandial data up to week 4 in a phase 4, single-center, randomized, cross-over, single-blind, placebo-controlled study. The primary end point was the change in 4-h glucose area under the concentration versus time curve [AUC (0–4 h)] from baseline to week 4. Secondary end points included changes from baseline in other PD parameters (insulin, C-peptide, glucagon, and triglycerides) at weeks 1, 2, and 4 and the safety and tolerability of dulaglutide 0.75 mg. Continuous glucose monitoring (CGM) during the 1st week was performed as an exploratory measure in each treatment period. Results The decrease in AUC (0–4 h) from baseline to week 4 following dulaglutide administration was statistically significant compared with placebo at weeks 1, 2, and 4 ( P  < 0.0001). Insulin and C-peptide levels were also significantly increased ( P  < 0.05) with dulaglutide versus placebo at weeks 2 and 4. There were no statistically significant differences between groups in glucagon and triglyceride levels. Daily average glucose concentrations were decreased on the day after the first administration of dulaglutide and remained at similar levels for 4 days. The incidence of treatment-emergent adverse events was slightly higher with dulaglutide versus placebo. Conclusion In conclusion, dulaglutide decreased postprandial glucose from week 1 in Japanese patients with T2D, indicating that dulaglutide treatment is associated with favorable PD effects soon after treatment begins. Trial Registration ClinicalTrials.gov identifier: NCT03315780. Funding Eli Lilly Japan K.K. (Kobe, Japan).

We present a case report of propiverine-induced Parkinsonism. We previously reported the induction of catalepsy by amiodarone, aprindine and procaine, which possess a diethylaminomethyl moiety and demonstrated selective blockade of dopamine D2 receptors by these drugs in mice. We hypothesized that drugs possessing a diethylaminomethyl structure may generally induce Parkinsonism and/or catalepsy. Thus, we performed a study to examine whether oxybutynin, pentoxyverine and etafenone, as well as propiverine, induce catalepsy in mice. The intensity of drug-induced catalepsy was in the order: haloperidol > etafenone > pentoxyverine > propiverine > oxybutynin. In vivo occupancy of dopamine D1, D2 and mACh receptors in the striatum was also examined. The in vitro binding affinities to the D1, D2 and mACh receptors in the striatum synaptic membrane were within the ranges of 2.4-140 microM, 380-4,200 nM, and 1.2-2,800 nM, respectively. These results support the idea that any drug possessing a diethylaminomethyl moiety may contribute to the induction of catalepsy, possibly by occupying dopamine receptors.