An Investigation in the Comparability of the Exposure and Recommended Dose of Selected Pfizer Drugs in East Asian Countries: Is Mutual Usage of Clinical Data Among East Asian Countries Feasible?

The current regulatory path for new drug registration in East Asian countries has led to significant delay of the new medicines in these countries. A unified regulatory path and allowance of mutual usage of clinical data in East Asian countries would lead to cost saving in drug development and expedite the new drug registration in these countries. The objectives of the present analysis are to compare the approval dates of a selection of products developed by Pfizer in the United States and East Asian countries (China, Japan, Korea) and compare the pharmacokinetics and recommended doses of these products in East Asian countries. Eighteen products (20 drugs, 2 products with 2 combination drugs) with exposure data available in at least 2 of the 3 East Asian countries across different therapeutic areas were included in the analyses. The results showed that most products had delayed approval in East Asian countries (up to 8 years) after US or EU approval. No distinct differences were observed in the drug exposure and recommended doses for the selected products in East Asian countries. These results together with literature data of genetic similarity of the East Asian populations support the mutual usage of the clinical data in the East Asian countries for expedited regulatory submission and approval.

A High-Certainty Visual Servo Control Method for a Space Manipulator with Flexible Joints.

This paper introduces a novel high-certainty visual servo algorithm for a space manipulator with flexible joints, which consists of a kinematic motion planner and a Lyapunov dynamics model reference adaptive controller. To enhance kinematic certainty, a three-stage motion planner is proposed in Cartesian space to control the intermediate states and minimize the relative position error between the manipulator and the target. Moreover, a planner in joint space based on the fast gradient descent algorithm is proposed to optimize the joint's deviation from the centrality. To improve dynamic certainty, an adaptive control algorithm based on Lyapunov stability analysis is used to enhance the system's anti-disturbance capability. As to the basic PBVS (position-based visual servo methods) algorithm, the proposed method aims to increase the certainty of the intermediate states to avoid collision. A physical experiment is designed to validate the effectiveness of the algorithm. The experiment shows that the visual servo motion state in Cartesian space is basically consistent with the planned three-stage motion state, the average joint deviation index from the centrality is less than 40%, and the motion trajectory consistency exceeds 90% under different inertial load disturbances. Overall, this method reduces the risk of collision by enhancing the certainty of the basic PBVS algorithm.

A Reference-Scaled Average Bioequivalence Study of Azithromycin Tablets Manufactured in China and the United States: An Open-Label, Randomized, Single-Dose, 3-Way Crossover Study in Healthy Chinese Subjects Under Fasted and Fed Conditions.

Azithromycin (Zithromax) is an azalide antibiotic that binds to the 50S ribosomal subunit of the susceptible organism and thereby interferes with its protein synthesis. An open-label, randomized, single-dose, 3-way crossover bioequivalence study was conducted to compare the rate and extent of absorption of the azithromycin 250-mg tablet manufactured at Pfizer Dalian (China) and that at Pfizer Barceloneta (United States) under fasted and fed conditions in healthy Chinese subjects. This study aimed to support a generic consistency evaluation program, initiated by the National Medical Products Administration, for evaluating the quality and efficacy of the products manufactured in China. In the study, the within-subject standard deviation for area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fasted condition was <0.294, and the 90%CI for the ratio was within 80% to 125%; the within-subject SDs for serum peak concentration in the fasted condition, area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fed condition, and serum peak concentration in the fed condition, were all >0.294, with the upper confidence bounds being <0.00, and the point estimates of the ratios being within 80% to 125%. The results support the bioequivalence between azithromycin tablets manufactured in China and the United States in fasted and fed conditions, with both tablets showing an acceptable safety/tolerability profile in the studied population.

Bioequivalence Evaluation Between Acarbose and Metformin Fixed-Dose Combination and Corresponding Individual Components in Healthy Chinese Male and Female Subjects.

Acarbose and metformin have been recommended both as monotherapy and add-on therapy in type 2 diabetes mellitus. A novel fixed-dose combination (FDC) of acarbose and metformin has been developed to improve compliance and patient adherence to therapy. The current study investigated the bioequivalence (BE) between acarbose/metformin FDC (50 mg/500 mg) with corresponding loose combination of individual components under fasting conditions in healthy Chinese male and female subjects, using a randomized, 2-period, 2-way crossover study design. Pharmacodynamic parameters of serum glucose ratio between treatment day and baseline (ratio of maximum concentration [Cmax ], day 1/Cmax , day -1 and ratio of area under the concentration-time curve [AUC] from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1) were used as the primary variables to evaluate BE of acarbose. Pharmacokinetic parameters Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC were used to evaluate BE of metformin. The results showed that the 90% confidence intervals of the ratios of all primary target variables including ratio of Cmax , day 1/Cmax , day -1 and ratio of AUC from time 0 to 4 hours, day 1/AUC from time 0 to 4 hours, day -1 for acarbose, and Cmax , AUC from time 0 to the last data point greater than the lower limit of quantification, and AUC for metformin all fell within the acceptance limits of 0.8 to 1.25. Thus, BE between 50-mg acarbose and 500-mg metformin as an FDC and loose combination was established. Furthermore, different kinds of exploratory pharmacodynamic parameters (based on either serum glucose or insulin) including several newly proposed parameters were also investigated for acarbose BE evaluation in this study, and inconsistent results were observed.

Design and Experimental Study of Space Continuous Robots Applied to Space Non-Cooperative Target Capture.

Space capture actuators face problems such as insufficient flexibility and electrical components that are vulnerable to extreme space environments. To address these problems, a centralized-driven flexible continuous robot based on a multiple scissor mechanism units is proposed in this study. The continuous robot body is composed of two scissor mechanism units coupled in series, and the base container's three motors to drive the robot. The two scissor mechanism units ensure a wide range of flexible operations and the light weight of the robot. The centralized drive with three motors not only reduces the number of driving sources, but also ensures temperature control and protection of electrical components in the space environment. The kinematics and dynamics of the robot are analyzed, and the workspace and deformation performance of the robot are verified through experiments. Compared with other continuous robots, the proposed continuous robot retains the characteristics of continuous robots in a wide range of flexible operations. At the same time, the configuration is light and a small number of driving sources are used, which is suitable for extreme temperatures, vacuum, radiation, and strict resource-constrained environments in space.

Investigation of bioequivalence, safety, and tolerability of a fixed-dose combination of nifedipine GITS and candesartan compared with the corresponding loose-dose combination under fed conditions
.

OBJECTIVE: To investigate the bioequivalence, safety, and tolerability of single-dose nifedipine gastrointestinal therapeutic system (GITS) and candesartan as a fixed-dose combination (FDC) relative to the loose combination in healthy males under fed conditions. MATERIALS AND METHODS: A total of 48 subjects received nifedipine GITS 60 mg and candesartan 32 mg as an FDC or loose combination in an open-label, 2-way crossover, 2-treatment sequence design, with a washout of at least 5 days between treatments. Study medications were administered following an overnight fast of at least 10 hours, and 30 minutes after ingestion of a high-fat test meal. Plasma samples were collected at intervals over a 48-hour period post-dosing. Safety and tolerability parameters were documented throughout the study. RESULTS: For nifedipine, 90% confidence intervals (CIs) for the ratios of FDC/loose combination were within acceptance limits of bioequivalence (i.e., 80 - 125%) for both AUC0-tlast (91.36%; 111.5%) and Cmax (87.93%; 100.5%). For candesartan, 90% CIs for the ratios of FDC/loose combination were within acceptance limits for AUC0-tlast (112.8%; 124.4%), but not for Cmax (120.5%; 137.8%). There were no serious adverse events (AEs) or AEs leading to treatment discontinuation and no clinically relevant changes in vital signs or laboratory parameters. CONCLUSION: A single dose of the FDC-containing nifedipine GITS 60 mg and candesartan 32 mg, when compared to the corresponding loose combination under fed conditions, met the criterion for bioequivalence based on AUC0-tlast, while the slightly higher Cmax for candesartan is not considered clinically relevant. The FDC displayed safety and tolerability profiles similar to the loose combination.

A Highly Reliable Embedded Optical Torque Sensor Based on Flexure Spring.

We propose a new highly reliable and lightweight embedded optical torque sensor for biomimetic robot arm enabling the torque measurement in joints, which can measure torque of the joint by detecting torsion of its elastic element (mechanical structure or flexure element). Flexure spring is introduced as the elastic element of the torque sensor in this paper. Because of its curve modeling, flexure spring is not inclined to be broken contrast to crossbeam structure, which is commonly used in torque sensor. Thanks to this structure, we can build a torque sensor as an extremely compact and highly reliable size. Six types of flexure spring are proposed to be used as the elastic element of the torque sensor in this paper, which have the potential for the requirements of measurement range and multidimensional detection. The optical electronic, less influenced by electromagnetic interferences, is selected to measure the torsion displacement of the flexure spring. The proposed design is analyzed, which can obtain the successful measurement of the torque with a load capacity of 1 Nm. One of the designed optical torque sensors is optimized by FEM. The calibration and experiment are conducted to ensure its feasibility and performance.

Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.

The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.

Pharmacokinetics and safety of nifedipine GITS/candesartan fixed-dose combination in subjects with hepatic impairment
.

OBJECTIVE: To investigate the pharmacokinetic (PK) profiles and safety of nifedipine and candesartan after a single oral dose of nifedipine gastrointestinal therapeutic system (GITS) 30 mg/candesartan cilexetil 8 mg (N30/C8 mg) fixed-dose combination (FDC) in adults with mild to moderate hepatic impairment. METHODS: A phase I, single-center, non-randomized, non-controlled, non-blinded, observational study (N = 32). PK profiles for nifedipine and candesartan were assessed in patients with mild (Child-Pugh A; group 1) or moderate (Child-Pugh B; group 2) hepatic impairment and compared with age- and gender-matched healthy controls (groups 3 and 4) following a single dose of N30/C8 FDC. Safety and tolerability were assessed throughout the study. RESULTS: On average, area under the plasma concentration vs. time curves (AUC) for nifedipine increased 93% and 253% in mild and moderate hepatic impairment, while maximum plasma concentrations (Cmax) increased 64% and 171%, respectively. AUC values for candesartan increased 19% and 92%, while Cmax values increased 3% and 11%, respectively. In subjects with or without liver impairment, adverse event rates were similar and consistent with the known side-effect profiles of nifedipine GITS and candesartan as monotherapies. CONCLUSIONS: Careful monitoring, and, if necessary, dose adjustment according to response and tolerability may be required for nifedipine GITS/candesartan FDC in patients with mild and moderate hepatic impairment.
.

Safety and pharmacokinetic studies of silodosin, a new α1A-adrenoceptor selective antagonist, in healthy Chinese male subjects.

The objectives of the study were to assess the safety and pharmacokinetics of silodosin capsules in 82 healthy male Chinese subjects. To evaluate the safety after single-dosing escalation, 40 subjects were equally divided into 4 groups (2, 4, 8, 12 mg) by a randomized, double-blind and placebo-controlled design. To assess the pharmacokinetics after single-dosing, 30 subjects were equally divided into 3 groups (4, 8, 12 mg). To assess the safety and pharmacokinetics via multiple-dosing, 12 subjects were included as a group (4 mg once daily at day 1 and day 7; 4 mg twice daily at day 2 through day 6). The safety observations showed that mild adverse events, including postural hypotension, dizziness, and headache, were observed. After single-dosing at doses of 4, 8, and 12 mg, the mean area under the concentration-time curve from 0 to 36 h (AUC(0-36)) values were 136.82±46.38, 270.17±54.66, and 474.63±108.50 µg/l·h and the mean maximal silodosin concentration in plasma (C(max)) values were 26.70±7.48, 48.47±12.35, and 94.07±22.59 µg/l, respectively. After multiple-dosing, the C(max) value at day 7 was 33.84±19.54 µg/l, and the AUC(0-24) value at day 7 was 193.19±68.96 µg/l·h. The accumulation ratio of the AUC value was 1.55 by comparing the multiple-dosing with the single-dosing. It is concluded that silodosin is safe and tolerated in healthy Chinese male subjects at the dosing levels used in this study. The mean C(max) and AUC values of silodosin increased proportionally with dose escalation, showing characteristics of linear pharmacokinetics.

Chronopharmacology of angiotensin II-receptor blockers in stroke-prone spontaneously hypertensive rats.

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.

Chronopharmacology of Angiotensin II-receptor Blockers in Stroke-Prone Spontaneously Hypertensive Rats.

Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.

Protective effect of amlodipine against osteoporosis in stroke-prone spontaneously hypertensive rats.

Hypertensive patients have an increasing risk of osteoporosis. A recent case-controlled study has demonstrated that anti-hypertensive therapy reduced a risk of fracture in these patients. In this study, we investigated whether amlodipine protects against the reduction in bone density in stroke-prone spontaneously hypertensive rats (SHR-sp). Oral dosing of amlodipine (0.5 and 3.0mg/kg/day) was started when SHR-sp were 3 months old, and continued for 3 months. At the end of the experiment, bone density of femur and serum concentrations of calcium, parathyroid hormone (PTH) and C-telopeptide of type I collagen (CTx), reflecting osteoclast activity, were measured. The bone density dose-dependently increased by the treatment with amlodipine. In addition, amlodipine reduced serum concentrations of calcium, PTH and CTx. This study showed that amlodipine prevents the reduction in bone density during the repeated dosing in SHR-sp. Amlodipine might exert its effect through a direct inhibition of osteoclast function and/or suppression of PTH secretion and subsequent inhibition of osteoclast activity.

Determination of silodosin in human plasma by liquid chromatography-tandem mass spectrometry.

A rapid, sensitive and specific liquid chromatography-tandem mass spectrometric (LC-MS/MS) method has been developed and validated for the determination of silodosin in human plasma. Silodosin and internal standard (IS) were extracted from human plasma by liquid-liquid extraction using methyl t-butyl ether and analyzed on an Agilent C(8) column with the mobile phase of acetonitrile-10 mM ammonium acetate (40:60, v/v) adjusted to pH 4.5 with acetic acid. Detection was carried out by MS/MS using TurboIonSpray (TIS) ionization and multiple reaction monitoring (MRM) in the positive-ion mode. The mass transitions monitored were m/z 496.3-->261.4 and m/z 440.4-->259.3 for silodosin and IS, respectively. The standard curve was linear in the range of 0.50-50.0 ng/ml with intra- and inter-day precision of 3.2-7.2% and 2.0-7.5%, respectively. The lower limit of quantification (LLOQ) for silodosin was 0.50 ng/ml using 500 microl plasma sample. This method was successfully applied to the pharmacokinetic study in healthy volunteers.

Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects.

AIMS: To investigate the safety, pharmacokinetics and pharmacodynamics of rivaroxaban, an oral, direct Factor Xa (FXa) inhibitor, in healthy, male Chinese subjects. METHODS: Two randomized, single-blind, placebo-controlled, dose-escalation studies were conducted in healthy Chinese men aged 18-45 years. In the single-dose study, subjects received single, oral doses of rivaroxaban 2.5, 5, 10, 20 and 40 mg. In the multiple-dose study, oral rivaroxaban was administered in doses of 5, 10, 20 and 30 mg twice daily for 6 days. RESULTS: Rivaroxaban, in single and multiple doses up to 60 mg, was well tolerated. Rapid absorption was observed in both studies (time to C(max) 1.25-2.5 h). In the multiple-dose study, rivaroxaban exposure increased dose-proportionally after the first dose and at steady state (for the 5-20-mg doses). The half-life of rivaroxaban was up to 7.9 h in the single-dose study. Maximal inhibition of FXa activity was achieved within 1-3 h of dosing in the single-dose study [at 20 mg FXa inhibition as a median percentage change from baseline, 45.92; 95% confidence interval (CI) 44.64, 50.70] and 2-3 h after administration at steady state in the multiple-dose study (at 20 mg median FXa inhibition as a median percentage change from baseline, 60.25; 95% CI 56.16, 63.05), in line with maximum rivaroxaban plasma concentrations. CONCLUSIONS: Rivaroxaban demonstrated predictable pharmacokinetics and pharmacodynamics in healthy Chinese subjects, in line with findings observed previously in White subjects. This suggests that fixed doses of rivaroxaban may be administered to all patients, regardless of their ethnic origin.

Pharmacological properties of SD-282 - an alpha-isoform selective inhibitor for p38 MAP kinase.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.

Antitumor activity of TGF-beta inhibitor is dependent on the microenvironment.

Pancreatic cancer is one of the deadliest forms of cancer and effective treatment remains a clinical challenge. Transforming growth factor-beta (TGF-beta) has important roles in primary tumor progression and in promoting metastasis, and has become an attractive target for therapy. Previously, we reported that treatment of pancreatic cancer cells in vitro with SD-208, a small molecule inhibitor of the TGF-beta receptor I kinase (TGF-betaRI), inhibited expression of genes associated with tumor progression and inhibited invasiveness in a cell-based assay. In a demonstration of efficacy of TGF-beta signaling inhibition in an in vivo model of pancreatic cancer, we showed significantly reduced primary tumor weight and decreased incidence of metastasis in the Panc-1 orthotopic xenograft model of established pancreatic cancer. In this report, we extend these in vivo findings to examine the mechanistic consequences of TGF-betaRI inhibition on Panc-1 primary tumors and their microenvironment in situ. In a longitudinal study of TGF-betaRI inhibition in the Panc-1 orthotopic model, we show that SD-208 treatment significantly reduced tumor growth measured as bioluminescence intensity throughout the study. Histological evaluation revealed that SD-208 treatment reduced proliferation and induced apoptosis in the primary tumors, and reduced fibrosis in the tumor microenvironment. An immune contribution (greater B-cell infiltration in SD-208-treated tumors) was also suggested by the histological analyses. SD-208 not only blocked direct TGF-beta signaling in Panc-1 primary tumors (reduced phospho SMAD2/3), but also down-regulated the expression of TGF-beta-regulated genes (PAI-1 and COL7A1). Taken together, our results indicate that a TGF-betaRI kinase inhibitor has a potential therapeutic benefit for pancreatic cancer patients.

Transforming growth factor-beta receptor type 1 (TGFbetaRI) kinase activity but not p38 activation is required for TGFbetaRI-induced myofibroblast differentiation and profibrotic gene expression.

Transforming growth factor-beta (TGFbeta) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFbeta also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFbetaRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFbetaRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFbeta-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGFbeta-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.

Preventive and therapeutic potential of p38 alpha-selective mitogen-activated protein kinase inhibitor in nonobese diabetic mice with type 1 diabetes.

Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38alpha MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immuno-histochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5+ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38alpha-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38alpha-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.