Key factors for overcoming psychological insulin resistance: A qualitative study in Japanese people with type 2 diabetes.

AIMS: We report the key factors that motivate reluctant Japanese people with type 2 diabetes (T2D) to initiate insulin treatment. METHODS: Participants were asked questions pertaining to 2 primary areas of exploration in a concurrent mixed methods approach: (a) understanding people's thoughts and perceptions before and after insulin initiation and any related factors; and (b) exploring the reasons behind people's responses. Data were analyzed using Steps for Coding and Theorization. RESULTS: Participant responses broadly related to 3 themes which influence insulin initiation; 1. Advice from a health care provider (HCP) that insulin is an appropriate treatment; 2. Demonstration by HCPs on how to use the insulin pen/needle and the injection process; and 3. Resignation/surrender/acceptance of insulin, where participants felt there was no other choice but to commence insulin. CONCLUSIONS: Based on the 3 identified themes, it is important for HCPs to explain the benefits of insulin and demonstrate and explain the injection procedure to reluctant Japanese people with T2D. We also identified resignation/surrender/acceptance of insulin as a reason for treatment commencement. This study provides important information to assist HCPs in helping reluctant Japanese people with T2D to initiate basal insulin therapy.

Treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine is comparable in patients with type 2 diabetes mellitus after switching from insulin glargine or insulin degludec: a post-marketing safety study.

OBJECTIVE: To evaluate insulin treatment satisfaction, safety, and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice for Japanese patients with type 2 diabetes mellitus (T2DM) who switched from originator insulin glargine (100 U/mL) or insulin degludec treatment to GLY treatment. METHODS: The Insulin Treatment Satisfaction Questionnaire (ITSQ) was used to assess treatment satisfaction in a subgroup analysis of a post-marketing safety study. Hypoglycemia incidence rates and blood glucose control are also reported during the 12-month observation period for GLY-switched patients. RESULTS: Of 1104 patients with T2DM enrolled to participate, 565 patients switched from either insulin glargine U100/mL (n = 470) or insulin degludec (n = 95) to GLY. The mean total change from baseline to 3 months for total ITSQ score was 1.35 (95% confidence interval [CI] - 0.13 to 2.83, p = .073) for patients who switched from insulin glargine and 2.63 (95% CI -1.43 to 6.70, p = .195) for patients who switched from insulin degludec to GLY treatment. The mean change from baseline to 12 months in hypoglycemia events reported per month was -0.04% (95% CI -0.12 to 0.03, p = .236) for patients who switched from insulin glargine and no change for patients who switched from insulin degludec (0.00, 95% CI -0.20 to 0.20, p = 1.000). Non-significant mean changes from baseline to 12 months were observed for hemoglobin A1c and fasting plasma glucose in GLY-switched patients. CONCLUSIONS: Treatment satisfaction does not change significantly in Japanese patients with T2DM who switch to GLY from the reference product or from insulin degludec. Safety and effectiveness over a 12-month period were similar in GLY-treated patients who switched from either insulin glargine or insulin degludec. CLINICALTRIALS.GOV: Not applicable.

Long-term safety and effectiveness of biosimilar insulin glargine in Japanese patients with diabetes mellitus in routine clinical practice: results of a post-marketing safety study.

Objective: To evaluate the long-term safety and effectiveness of biosimilar insulin glargine (GLY) in real-world clinical practice.Methods: This prospective, non-interventional, multicenter, observational, post-marketing safety study (PMSS) enrolled Japanese patients with type 1 or 2 diabetes mellitus (T1DM or T2DM) starting GLY therapy, and was required by Japanese Pharmaceutical Affairs Law mandating post-marketing safety surveillance to acquire safety and effectiveness data of biosimilar products. Data collected from the 12-month observation included patient characteristics, adverse events, and blood glucose control.Results: The study enrolled 141 patients with T1DM and 1104 patients with T2DM. Pre-study insulin was used by 94.1% of patients with T1DM and 75.0% with T2DM. 65.4% of patients with T1DM and 64.3% with T2DM switched from the reference product (GLY-switched), while 25.0% with T2DM were insulin-naive. Adverse events were reported by 5.7% and 8.5% in T1DM and T2DM, respectively. Similar incidences were reported in GLY-switched. Adverse events were reported by 10.7% in insulin-naive T2DM. Baseline mean hypoglycemic events/month were 1.8 and 0.1 in T1DM and T2DM, respectively: the mean change from baseline (CFB) was -1.2 (p = .066) and 0.0 (p = .915), respectively. Baseline mean HbA1c was 8.4% and 8.7% in T1DM and T2DM, respectively; the mean CFB was -0.5% (p < .001) and -0.9% (p < .001), respectively, and -1.5% (p < .001) in insulin-naive T2DM.Conclusions: This first long-term Japanese PMSS of GLY demonstrated adverse events, hypoglycemia, and glycemic control consistent with the known GLY profile for T1DM and T2DM patients, in routine clinical practice.

Successful Healthcare Provider Strategies to Overcome Psychological Insulin Resistance in Japanese Patients with Type 2 Diabetes.

INTRODUCTION: EMOTION was a multinational, noninterventional study surveying current insulin-using adults with type 2 diabetes mellitus (T2D) who were initially reluctant to begin insulin treatment. In this Japanese population subanalysis of EMOTION, we identify the frequency and level of helpfulness of healthcare provider (HCP) actions, and we analyze life events ('actions/events') that assist T2D patients with psychological insulin resistance in the decision to initiate insulin. METHODS: Participants were selected from Survey Sampling International and their local partners' market research panels in Japan. Quantitative surveys were administered between December 2016 and August 2017 to patients who met the study criteria. Participants were asked whether 45 actions/events occurred, and to rate the level of helpfulness of the actions/events in contributing to their decision to initiate insulin. RESULTS: Among the 594 eligible participating adults in the EMOTION study, 99 were from Japan. Despite initial reluctance to begin insulin treatment, 80.8% of the Japanese participants immediately commenced insulin. Practical demonstrations by HCPs on how to use insulin were rated by participants as most helpful. Examples of such practical demonstrations, reported as helping moderately or a lot, were 'HCP walked patient through the process of exactly how to take insulin' (82.8%), 'HCP showed an insulin pen' (79.7%), and 'HCP helped patient to see how simple it was to inject insulin' (79.1%). CONCLUSION: This study identifies actions that HCPs can use to assist Japanese patients in deciding whether to initiate insulin. These findings may aid the development of clinical interventions addressing reluctance to begin insulin treatment among Japanese patients with T2D. FUNDING: Eli Lilly and Company and Boehringer Ingelheim. Plain language summary available for this article.

The increasing prevalence of type 2 diabetes mellitus (T2D) is a major health concern globally. In Japan, the prevalence of diabetes is predicted to increase over the next decades. Insulin is a hormone which keeps blood glucose levels within the normal range. People with diabetes often require insulin therapy as they do not make sufficient insulin, or the insulin that is produced does not work optimally. Many patients delay insulin therapy due to a variety of factors. Reluctance to begin insulin treatment is known as 'psychological insulin resistance' (PIR). Several studies have described recommendations to address PIR, but there is little research regarding effective strategies that help reluctant patients begin insulin. Reports describing PIR among Japanese patients are limited. EMOTION was a multinational study surveying insulin-using adults with T2D and initial PIR. We report a Japanese population subanalysis of EMOTION, identifying factors which help reluctant Japanese patients begin insulin therapy. Our results indicate that healthcare provider (HCP) actions are associated with a patient's decision to use insulin. Practical demonstrations by HCPs on how to use insulin were reported as most helpful. Reassurance concerning pain of injection, explanations regarding blood glucose numbers and future health, encouragement to make contact in case of any problems, and occurrence of a positive life event were also rated by Japanese participants as being helpful in deciding to commence insulin. This study provides important information on actions that can be used by HCPs to treat Japanese patients with T2D who are reluctant to begin insulin treatment.

Similar Intrapatient Blood Glucose Variability with LY2963016 and Lantus® Insulin Glargine in Patients with Type 1 (T1D) or Type 2 Diabetes, Including a Japanese T1D Subpopulation.

INTRODUCTION: LY2963016 insulin glargine (LY IGlar) and Lantus® (IGlar), both with identical primary amino acid sequences, were compared in two phase 3 studies for intrapatient blood glucose variability. METHODS: ELEMENT-1 was a 52-week study in patients with type 1 diabetes (T1D), which included Japanese patients, and ELEMENT-2 was a 24-week study in non-Japanese patients with type 2 diabetes (T2D). In ELEMENT-1, 535 patients with T1D were evaluable (268 LY IGlar and 267 IGlar). Of these, 100 were Japanese patients (49 LY IGlar and 51 IGlar). In ELEMENT-2, 756 patients with T2D were evaluable (376 LY IGlar and 380 IGlar). We evaluated and compared intrapatient blood glucose variability of LY IGlar and IGlar in these studies from three different perspectives: intrapatient between-day fasting blood glucose variability, intrapatient between-day daily mean blood glucose variability, and intrapatient within-day blood glucose variability. RESULTS: Overall, evaluations of all three indices showed that intrapatient blood glucose variability was similar between LY IGlar and IGlar throughout the study periods both in the overall populations of patients with T1D and T2D and also in the subgroup of Japanese patients with T1D. CONCLUSION: Intrapatient blood glucose variability between LY IGlar and IGlar was shown to be similar in patients with T1D or T2D. CLINICAL TRIAL REGISTRATION: NCT01421147 (ELEMENT-1) and NCT01421459 (ELEMENT-2). FUNDING: Eli Lilly and Company (Indianapolis, IN, USA); Boehringer-Ingelheim (Ridgefield, CT, USA); Eli Lilly Japan K.K. (Kobe, Japan) and Nippon Boehringer Ingelheim Co., Ltd. (Tokyo, Japan).

Efficacy and safety of subgroup analysis stratified by baseline HbA1c in a Japanese phase 3 study of dulaglutide 0.75 mg compared with insulin glargine in patients with type 2 diabetes.

The efficacy and safety of once-weekly dulaglutide 0.75 mg (dulaglutide) compared with once-daily insulin glargine (glargine) in Japanese patients with type 2 diabetes were evaluated according to subgroups stratified by baseline glycated hemoglobin (HbA1c) (≤8.5% or >8.5%). This exploratory analysis of a randomized, open-label, phase 3 study included 361 patients. In both HbA1c subgroups (patients with baseline HbA1c ≤8.5% or >8.5%), a statistically significantly greater reduction in HbA1c was observed in dulaglutide-treated patients compared with glargine-treated patients after 26 weeks of treatment (HbA1c ≤8.5%: dulaglutide, -1.27%; glargine, -0.72%; HbA1c >8.5%: dulaglutide, -2.04%; glargine, -1.47%; p < 0.001 for both). Mean body weight was decreased from baseline in both subgroups of the dulaglutide group and increased in both subgroups of the glargine group; there were statistically significant differences between the treatment groups in both subgroups (p < 0.05 for both). In both subgroups, similar reductions in fasting blood glucose were observed for dulaglutide- and glargine-treated patients, and a greater reduction in postprandial blood glucose was observed for dulaglutide-treated patients compared with glargine-treated patients. Although dulaglutide increased gastrointestinal adverse events compared with glargine in both subgroups, all gastrointestinal events of diarrhea, nausea, constipation, and vomiting in dulaglutide-treated patients were mild in intensity and well tolerated. In both subgroups, there was a lower incidence of hypoglycemia with dulaglutide than with glargine. Dulaglutide demonstrated significantly greater HbA1c reduction compared with glargine, with an acceptable safety profile, regardless of baseline HbA1c.

Extension of recovery time from fatigue by repeated rest with short-term sleep during continuous fatigue load: Development of chronic fatigue model.

Homeostasis is known to be involved in maintaining the optimal internal environment, helping to achieve the best performance of biological functions. At the same time, a deviation from optimal conditions often attenuates the performance of biological functions, and such restricted performance could be considered as individual fatigue, including physical and mental fatigue. The present study seeks to develop an animal model of chronic or subacute fatigue in which the recovery time is extended through the gradual disruption of homeostasis. We show that repeated short-term rest periods with certain lengths of sleep during continuous fatigue loading extend recovery from spontaneous nighttime activity but not physical performance in comparison with a continuous fatigue-loading procedure. Furthermore, the immobility time in a forced swimming test was extended by repeated short-term rests. These results suggest that repeated short-term rest with certain lengths of sleep during continuous fatigue loading is able to extend the recovery from mental fatigue but not from physical fatigue and that this effect might occur via the disruption of a homeostatic mechanism that is involved in restoring the optimal internal environment.

Exploration of Antiemetics for Osteoporosis Therapy-Induced Nausea and Vomiting Using PET Molecular Imaging Analysis to Gastrointestinal Pharmacokinetics.

PURPOSE: To select appropriate antiemetics relieving teriparatide-induced nausea and vomiting during osteoporosis treatment using PET molecular imaging and pharmacokinetic analysis. METHODS: Rats were pretreated with subcutaneous teriparatide, followed by oral administration of antiemetics with different pharmacological effects. The pharmacokinetics of antiemetics were assessed by oral administration of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) under free moving conditions in vivo. The effect of teriparatide on the permeability of Caco-2 cell membranes to [(18)F]FDG was assessed in vitro. The effects of antiemetics on teriparatide-induced suppression of gastrointestinal motility in vivo was assayed by positron emission tomography (PET) using orally administered [(18)F]FDG. RESULTS: Teriparatide delayed the time-radioactivity profile of [(18)F]FDG in blood and significantly reduced its absorption rate constant (k a ), determined from non-compartmental analysis, to 60% of control. In contrast, co-administration of granisetron or mosapride restored the time-radioactivity profile and k a of [(18)F]FDG to control levels. Teriparatide had no effect on Caco-2 membrane permeability to [(18)F]FDG. Pharmacokinetic PET imaging data analysis quantitatively showed the pharmacological effects of teriparatide-induced suppression of upper gastrointestinal motility and its restoration by granisetron and mosapride. CONCLUSIONS: Teriparatide-induced abdominal discomfort might be attributed to GI motility, and PET imaging analysis is a useful tool to for the selection of appropriate antiemetics.

Visualization and Quantitative Assessment of the Brain Distribution of Insulin through Nose-to-Brain Delivery Based on the Cell-Penetrating Peptide Noncovalent Strategy.

Our recent work suggested that intranasal coadministration with the cell-penetrating peptide (CPP) penetratin increased the brain distribution of the peptide drug insulin. The present study aimed to distinctly certify the ability of penetratin to facilitate the nose-to-brain delivery of insulin by quantitatively evaluating the distribution characteristics in brain using radioactive (64)Cu-NODAGA-insulin. Autoradiography and analysis using a gamma counter of brain areas demonstrated that the accumulation of radioactivity was greatest in the olfactory bulb, the anterior part of the brain closest to the administration site, at 15 min after intranasal administration of (64)Cu-NODAGA-insulin with l- or d-penetratin. The brain accumulation of (64)Cu-NODAGA-insulin with penetratin was confirmed by ELISA using unlabeled insulin in which intact insulin was delivered to the brain after intranasal coadministration with l- or d-penetratin. By contrast, quantification of cerebrospinal fluid (CSF) samples showed increased insulin concentration in only the anterior portion of the CSF at 15 min after intranasal coadministration with l-penetratin. This study gives the first concrete proof that penetratin can accelerate the direct transport of insulin from the nasal cavity to the brain parenchyma. Further optimization of intranasal administration with CPP may increase the efficacy of delivery of biopharmaceuticals to the brain while reducing the risk of systemic drug exposure.

Visualization of drug translocation in the nasal cavity and pharmacokinetic analysis on nasal drug absorption using positron emission tomography in the rat.

We performed positron emission tomography (PET) using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) to evaluate the pharmacokinetics of nasal drug absorption in the rat. The dosing solution of [(18)F]FDG was varied in volume (ranging from 5 to 25 µl) and viscosity (using 0% to 3% concentrations of hydroxypropylcellulose). We modeled the pharmacokinetic parameters regarding the nasal cavity and pharynx using mass balance equations, and evaluated the values that were obtained by fitting concentration-time profiles using WinNonlin® software. The regional nasal permeability was also estimated using the active surface area derived from the PET images. The translocation of [(18)F]FDG from the nasal cavity was visualized using PET. Analysis of the PET imaging data revealed that the pharmacokinetic parameters were independent of the dosing solution volume; however, the viscosity increased the absorption rate constant and decreased the mucociliary clearance rate constant. Nasal permeability was initially higher but subsequently decreased until the end of the study, indicating regional differences in permeability in the nasal cavity. We concluded that the visualization of drug translocation in the nasal cavity in the rat using PET enables quantitative analysis of nasal drug absorption, thereby facilitating the development of nasal formulations for human use.

Quantitative Evaluation of mMate1 Function Based on Minimally Invasive Measurement of Tissue Concentration Using PET with [(11)C]Metformin in Mouse.

PURPOSE: To evaluate the function of multidrug and toxin extrusion proteins (MATEs) using (11)C-labeled metformin ([(11)C]metformin) by positron emission tomography (PET). METHODS: PET was performed by intravenous bolus injection of [(11)C]metformin. Pyrimethamine at 0.5 and 5 mg/kg was intravenously administered to mice 30 min prior to the scan. Integration plot analysis was conducted for calculating liver (CLuptake,liver), kidney (CLuptake,kidney) tissue uptake, intrinsic biliary (CLint,bile) and urinary (CLint,urine) excretion clearances of [(11)C]metformin. RESULTS: Visualization by PET showed that pyrimethamine increased concentrations of [(11)C]metformin in the liver and kidneys, and decreased the concentrations in the urinary bladder without changing the blood profiles. Pyrimethamine had no effect on the CLuptake,liver and CLuptake,kidney, which were similar to the blood-flow rate. CLint,bile with regard to the liver concentration was unable to be determined, but administration of 0.5 and 5 mg/kg of pyrimethamine increased the liver-to-blood ratio to 1.6 and 2.3-fold, respectively, indicating that pyrimethamine inhibited the efflux of [(11)C]metformin from the liver. CLint,urine with regard to the corticomedullary region concentrations was decreased 37 and 68% of the control by administration of 0.5 and 5 mg/kg of pyrimethamine, respectively (P < 0.05). CONCLUSIONS: Tissue concentration based investigations using [(11)C]metformin by PET enables the functional analysis of MATEs in the liver and kidneys.

The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo.

In order to develop a new positron emission tomography (PET) probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1), (11)C-labelled metformin was synthesized and then evaluated as a PET probe. [(11)C]Metformin ([(11)C]4) was synthesized in three steps, from [(11)C]methyl iodide. Evaluation by small animal PET of [(11)C]4 showed that there was increased concentrations of [(11)C]4 in the livers of mice pre-treated with pyrimethamine, a potential inhibitor of MATEs, inhibiting the hepatobiliary excretion of metformin. Radiometabolite analysis showed that [(11)C]4 was not degraded in vivo during the PET scan. Biodistribution studies were undertaken and the organ distributions were extrapolated into a standard human model. In conclusion, [(11)C]4 may be useful as a PET probe to non-invasively study the in vivo function of hepatobiliary transport and drug-drug interactions, mediated by MATE1 in future clinical investigations.

Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats.

We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[(11)C]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([(11)C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance-associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [(11)C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [(11)C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [(11)C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake,kidney) were blood-flow-limited (73.6 ± 4.8 and 24.6 ± 0.6 ml/min per kilogram, respectively). Systemic elimination of [(11)C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [(11)C]DPV, which was 12.2 ± 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P < 0.05), respectively. These results indicate that [(11)C]DPV is taken up into the liver by organic anion-transporting polypeptides (rodent, Oatps; human, OATP) and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [(11)C]DPV. PET using [(11)C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine.

In vitro evaluation of the ciliary beat frequency of the rat nasal epithelium using a high-speed digital imaging system.

Mucociliary clearance (MC) is an important factor in determining nasal drug absorption and the ciliary beat of ciliated epithelial cells of the nasal mucosa is the driving force of MC. However, the relationship between MC and ciliary beat frequency (CBF) is still ambiguous. The purpose of this study was to establish an evaluation method of CBF as an index of mucociliary function and examine the relationship between MC and CBF. A sequence of images of ciliary beating of an excised rat nasal septum was captured using a high-speed digital video camera. CBF (beats per second, Hz) was determined from periodic changes in the contrast value of a specific location in a sequence of images. CBF under control conditions was 8.49±0.38 Hz, which is similar to values reported for cultured human nasal epithelial cells and rat tracheal cells. ß-Adrenergic and cholinergic antagonists decreased CBF, while ß-adrenergic agonists and acetylcholine increased CBF. These results were similar with those observed for MC in our previous study. It was found that CBFs were significantly and linearly correlated with MC, indicating that MC is directly regulated by CBF and that this evaluation system allows the quantitative determination of nasal mucociliary function.

Dynamic analysis of fluid distribution in the gastrointestinal tract in rats: positron emission tomography imaging after oral administration of nonabsorbable marker, [(18)F]Deoxyfluoropoly(ethylene glycol).

To develop potent drugs for oral use, information on their pharmacokinetic (PK) properties after oral administration is of great importance. We have recently reported the utility of positron emission tomography (PET) for the analysis of gastrointestinal (GI) absorption of radiolabeled compounds. In this study, PET image analysis was performed in rats using a novel PET probe, [(18)F]deoxyfluoropoly(ethylene glycol)s, with an average molecular weight of 2 kDa ([(18)F]FPEG), as a nonabsorbable marker to elaborate the GI physiology in more detail, such as segmental transition of the administered water, and fluid volume and distribution in the intestine. After oral administration of [(18)F]FPEG solution to rats, a 90 min PET scan with continuous blood sampling was performed, and then the disposition of radioactivity in each part of GI tract was investigated. From blood PK analysis, it was confirmed that the bioavailability of [(18)F]FPEG was quite low in rats. PET image analysis showed that the radioactivity after oral administration of [(18)F]FPEG solution rapidly passed through the stomach, spread into the proximal small intestine, and then transited toward the distal region of the small intestine without decreasing the radioactivity during GI transition. Radiometabolite analysis revealed that the radioactivity in intestinal mucosal tissues, blood, and urine was mainly derived from unchanged [(18)F]FPEG. It was also found that the volume of interest (VOI) after oral administration of the radiotracer enables an understanding of the time-dependent manner of effective fluid volume changes in the stomach and the small intestine. In addition, the rate constant of the intestinal transition of radioactivity in each intestinal segment was calculated by kinetic model analysis, which revealed that PET analysis enables us to determine the GI transit from the same individuals and that it is applicable to determine site-specific intestinal absorption. In conclusion, we demonstrated the high potency of PET imaging technique to elucidate the distribution of orally administered solution in the GI tract in vivo.

Dynamic analysis of GI absorption and hepatic distribution processes of telmisartan in rats using positron emission tomography.

PURPOSE: To dynamically analyze the processes of oral absorption and hepatobiliary distribution of telmisartan using positron emission tomography (PET). METHODS: (11)C-labeled telmisartan ([(11)C]TEL) was orally administered to rats with or without non-radiolabeled telmisartan (0.5, and 10 mg/kg). PET scanning of abdominal region and whole body was performed under conscious condition. In situ intestinal closed loop study in rats and in vitro permeation study in MDR1-MDCK II cell monolayers were also conducted. RESULTS: After oral administration of [(11)C]TEL, systemic bioavailability and hepatic distribution of radioactivity increased non-linearly with dose. In the intestinal lumen, both telmisartan and its glucuronide were detected and the ratio of telmisartan decreased dramatically at high dose of telmisartan. In situ closed loop study showed most of telmisartan-glucuronide detected in the intestinal lumen was derived from the bile excretion. In addition, in vitro permeation study revealed that telmisartan is a substrate of P-glycoprotein. CONCLUSION: PET imaging analysis successfully demonstrated the processes of intestinal absorption and hepatic distribution of telmisartan. PET study combined with appropriate in situ and in vitro experiments is highly expected to be a potent tool for better understanding of GI absorption and subsequent tissue distribution of various drugs and drug candidates.

Nasal delivery of P-gp substrates to the brain through the nose-brain pathway.

The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose-CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors.

Transnasal delivery of methotrexate to brain tumors in rats: a new strategy for brain tumor chemotherapy.

Brain tumors are one of the most lethal and difficult to treat. Their treatment is limited by the inadequate delivery of antitumor drugs to the tumor. In order to overcome this limitation, the possibility of the nose-brain direct transport pathway was evaluated using methotrexate (MTX) as a model antitumor agent. The direct transport of nasal MTX to the cerebrospinal fluid (CSF) was examined by comparing the concentration of MTX in the plasma and the CSF after intraperitoneal (IP) and intranasal (IN) administrations. The brain uptake of MTX was evaluated based on a multiple-time/graphical analysis by measuring the concentration of MTX in the plasma and in the brain. The feasibility of nasal chemotherapy was examined by three nasal dosings of MTX to tumor-bearing rats in vivo at two day intervals with peritoneal application as a positive control. MTX showed a significant inhibitory effect on the in vitro growth of 9L glioma cells with 50% growth inhibitory concentration at 7.99 ng/mL. The pharmacokinetic studies clarified the significant direct transport of MTX from nasal cavity both to the CSF and to the brain. Nasal chemotherapy with MTX significantly reduced the tumor weight as compared to nontreatment control and IP group. The strategy to utilize the nose-brain direct transport can be applicable to a new therapeutic system not only for brain tumors but also for other central nervous system disorders such as neurodegenerative diseases.

The transnasal delivery of 5-fluorouracil to the rat brain is enhanced by acetazolamide (the inhibitor of the secretion of cerebrospinal fluid).

The purpose of the research is to evaluate the effect of acetazolamide (AZA), an inhibitor of the secretion of cerebrospinal fluid (CSF), on the direct drug transport from the nasal cavity to the CSF and the brain uptake of a model drug, 5-fluorouracil (5FU). 5FU was infused intravenously or perfused nasally in the presence and absence of intravenously administered AZA. Concentrations of 5FU in plasma, CSF and the cerebral cortex were measured. The AUC and the concentration of 5FU in the brain were used to calculate the apparent brain uptake clearance (CL(up)) of 5FU, which is an index of drug delivery to the brain under the two experimental conditions. Intravenous AZA markedly increased the concentration of 5FU in the CSF and brain following the nasal perfusion of 5FU, although the plasma concentrations of 5FU were similar with intravenous infusion and nasal perfusions of 5FU. CL(up) of 5FU after the nasal perfusion with AZA was significantly increased by 104% and 46% as compared to intravenous infusion and nasal perfusion without AZA, respectively. AZA enhanced the 5FU delivery to the brain through a nose-to-brain pathway by increasing the concentration of the nasally applied drug in the CSF.

Assessment of the first and second generation antihistamines brain penetration and role of P-glycoprotein.

PURPOSE: The sedating effect of first generation H(1)-antihistamines has been associated with their ability to penetrate the blood-brain barrier (BBB) and lack of efflux by P-glycoprotein (Pgp). Second generation H(1)-antihistamines are relatively free of sedation and their limited brain penetration has been suggested to arise from Pgp-mediated efflux. The objective of this work was to evaluate the role of Pgp in brain penetration of first and second generation antihistamines. METHODS: Potential of antihistamines to be Pgp substrates was tested in vitro using Madin Darby canine kidney cells transfected with human Pgp. The role of Pgp in limiting brain penetration of antihistamines was tested by using the in situ brain perfusion technique. RESULTS: Majority of antihistamines were Pgp substrates in vitro. Following in situ brain perfusion, the first generation antihistamines substantially penetrated into rat brain independently from Pgp function. The second generation antihistamines terfenadine and loratadine, achieved substantial brain penetration, which was further enhanced by Pgp inhibition by cyclosporin A (CSA). In contrast, fexofenadine and cetirizine, penetrated brain poorly regardless of CSA administration. CONCLUSIONS: Antihistamines greatly differ in their ability to cross the BBB as well as in the role of Pgp in limiting their transport into the CNS in vivo.