Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects

We report here the preclinical anti-inflammatory profile of CS-706 [2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole], a novel cyclooxygenase-2 (COX-2) selective inhibitor. CS-706 selectively inhibited COX-2 in a human whole blood assay with an IC(50) of 0.31 microM, compared with an IC(50) of 2.2 microM for COX-1. The selectivity ratio of CS-706 was higher than those of the conventional non-steroidal anti-inflammatory drugs naproxen, indomethacin, and Diclofenac-Na, whereas it was lower than those of rofecoxib, valdecoxib and etoricoxib. It was similar to that of celecoxib. The pharmacokinetic profile of CS-706 showed rapid absorption and dose-proportional exposure after oral administration to rats. CS-706 inhibited prostaglandin E(2) production in inflamed tissue induced by yeast-injection in rats with potency similar to that of indomethacin. However, it inhibited gastric mucosal prostaglandin E(2) production in normal rats weakly compared with indomethacin. CS-706 ameliorated both yeast-induced inflammatory acute pain (ED(50)=0.0090 mg/kg) and adjuvant-induced chronic arthritic pain (ED(50)=0.30 mg/kg) in rats. CS-706 showed more potent antinociceptive activity than celecoxib and rofecoxib in these models. In an adjuvant-induced arthritic model in rats, CS-706 suppressed foot swelling prophylactically with an ID(50) of 0.10 mg/kg/day, and decreased foot swelling in the established arthritis therapeutically in a dose range of 0.040 to 1.0 mg/kg/day. Single administration of up to 100 mg/kg of CS-706 induced no significant gastric lesions in rats. In conclusion, CS-706 is a COX-2-selective inhibitor with a potent antinociceptive and anti-inflammatory activity and a gastric safety profile.     

Development of a predictive pharmacokinetic model for a novel cyclooxygenase-2 inhibitor

A predictive population pharmacokinetic model was developed for a novel cyclooxygenase-2 (COX-2) inhibitor CS-706, using data from 130 subjects in 3 phase 1 trials after single or multiple doses of CS-706 (2- to 800-mg doses daily, up to 14 days) and validated using sparse data from a separate study. A 2-compartment model described the data. Typical apparent clearance (CL/F) was 47.2 L/h and was reduced by 43% at doses greater than 200 mg. Apparent clearance was decreased by 38% in female subjects and by 64% and 15%, respectively, in poor/intermediate CYP 2D6 and poor CYP 2C9 metabolizers. Typical apparent volume of the central compartment was 166 L and increased with body weight. Bioavailability increased by 42% after nighttime doses and decreased saturably with increasing dose (50% reduction at 221 mg). Predicted exposures in Japanese subjects were reduced relative to whites because of a lower frequency of poor metabolizers. The model may aid in optimizing the design of future studies and predicting exposures in other subpopulations.     

Pharmacokinetics of repaglinide in healthy caucasian and Japanese subjects

The objective of this study was to investigate the pharmacokinetics of three different single doses (0.5, 1.0, and 2.0 mg) of repaglinide in healthy Caucasian and Japanese subjects. In this single-center, open-label, randomized, three-period crossover study, 27 healthy male subjects (15 Caucasian and 12 Japanese) each received three different single doses of repaglinide (0.5, 1.0, and 2.0 mg) at consecutive 24-hour intervals. Pharmacokinetic profiles, including area under the curve (AUC0-t), maximum serum concentration (Cmax), time to Cmax (tmax), and half-life (t1/2), were determined for each dose of repaglinide. The relative change in blood glucose level (RC1h) and area under the blood glucose curve (AUGC0-1) at 1 hour after dose were also measured. After oral dosing, both Cmax and AUC0-t increased linearly with dose within the 0.5- to 2.0-mg dose range, regardless of ethnic group. Both Cmax and AUC0-t were significantly higher in Japanese subjects than in Caucasian subjects. At each dose of repaglinide, Cmax and AUC were statistically significantly higher in Japanese than in Caucasian subjects (p = 0.0038 and 0.023, respectively). Discrepancies in body weight and body mass index (BMI) between Caucasian and Japanese subjects could not explain the between-group differences in Cmax or AUC0-t. Statistically significant differences in pharmacodynamic parameters (RC1h and AUGC0-1) were found between ethnic groups (p < 0.0001), the difference being more pronounced for RC1h than AUGC0-1. At a dose of 2.0 mg, the mean decrease in RC1h was 41% for Japanese subjects and 24% for Caucasian subjects. Hypoglycemic reactions were more common at the highest dose (2.0 mg), where they were observed more frequently in Japanese (7 cases) than in Caucasian subjects (4 cases). It was concluded that higher serum levels of repaglinide and greater reductions in blood glucose levels are found in Japanese than in Caucasian subjects following a single oral dose of repaglinide within the 0.5- to 2.0-mg dose range. Repaglinide is well tolerated in both ethnic groups. The results indicate that glycemic control targets may be achieved at lower doses within the recommended range (0.5-4.0 mg/meal) when repaglinide is used to treat Japanese patients in comparison to Caucasian patients.     

Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator

Pharmacokinetic (PK) and exposure-response modeling of a selective sphingosine 1-phosphate receptor-1 modulator (CS-0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2-compartment PK model with first-order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M-1) concentrations was modeled via an indirect response model, whereby M-1 inhibited the reentry of lymphocytes to the circulation. The indirect-response model based on SAD data had an Imax of approximately 85% and an IC50 of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model-based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.     

Aliskiren, a novel orally effective renin inhibitor, exhibits similar pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects

AIMS: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. This study compared the pharmacokinetic and pharmacodynamic properties of aliskiren in Japanese and Caucasian subjects. METHODS: In this open-label, single-centre, parallel-group, single- and multiple-dose study, 19 Japanese and 19 Caucasian healthy young male subjects received a single 300-mg oral dose of aliskiren on day 1 and then aliskiren 300 mg once daily on days 4-10. Blood samples were collected for the measurement of plasma aliskiren concentration, plasma renin concentration (PRC) and plasma renin activity (PRA). RESULTS: Pharmacokinetic parameters were comparable in Japanese and Caucasian subjects following administration of a single dose of aliskiren {ratio of geometric means: C(max) 1.12 [90% confidence interval (CI) 0.88, 1.43]; AUC(0-72 h) 1.19 [90% CI 1.02, 1.39]} and at steady state [mean ratio: C(max) 1.30 (90% CI 1.00, 1.70); AUC(0-tau) 1.16 (90% CI 0.95, 1.41)]. There was no notable difference in the plasma half-life of aliskiren between Japanese and Caucasian groups (29.7 +/- 10.2 h and 32.0 +/- 6.6 h, respectively). At steady state, peak PRC level and AUC for the concentration-time plot were not significantly different between Japanese and Caucasian subjects (P = 0.64 and P = 0.80, respectively). A single oral dose of aliskiren significantly reduced PRA to a similar extent in Japanese and Caucasian subjects (by 87.5% and 85.7%, respectively, compared with baseline; P < 0.01). Aliskiren was well tolerated by both ethnic groups. CONCLUSIONS: The oral renin inhibitor aliskiren demonstrated similar pharmacokinetic and pharmacodynamic properties in Japanese and Caucasian subjects.     

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean +/- SD: 34.5 +/- 16.6 versus 66.2 +/- 19.2 ng/mL, P < 0.01) and total area under the plasma concentration-time curve (490.1 +/- 277.5 vs 812.1 +/- 267.2 ng x h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.     

The effects of meloxicam, indomethacin or NS-398 on eicosanoid synthesis by fresh human gastric mucosa

BACKGROUND: In the stomach, constitutive cyclooxygenase (COX-1) synthesizes prostaglandins that maintain the integrity of the gastric mucosa, while their inhibition contributes to gastric mucosal damage. In contrast COX-2, an inducible enzyme, forms prostanoids involved in pain and inflammation. AIM: To compare prostaglandin synthesis inhibition by meloxicam, a selective COX-2 NSAID reported to have better gastric tolerability, with indomethacin and NS-398 in human gastric mucosa and in whole blood assays. METHODS: Meloxicam, indomethacin or NS-398 were incubated with fresh human gastric mucosa pieces (100 mg in 1 mL phosphate buffered saline, pH 7.4, 37 degrees C, 30 min), clotting human blood (1 mL, 37 degrees C, 60 min) or with lipopolysaccharide-stimulated heparinized blood (1 mL, 37 degrees C, 24 h). Prostanoids were analysed by radioimmunoassay. RESULTS: Meloxicam was a less potent inhibitor of gastric mucosal eicosanoid compared to indomethacin, showing a sixfold difference in IC50 with gastric mucosal prostaglandin E (PGE) (11.8 and 1.8 microM, respectively). In the whole blood assays, the COX-2/COX-1 ratio for meloxicam was 0.2 compared to 0.9 for indomethacin confirming meloxicam's COX-2 selectivity. CONCLUSION: The results with human mucosa pieces would suggest that the better gastric tolerability of meloxicam compared to indomethacin is related to its relatively lower inhibition of gastric mucosal PGE synthesis by COX-1.     

Involvement of peripheral cyclooxygenase-1 and cyclooxygenase-2 in inflammatory pain

Pain-induced functional impairment in the rat (PIFIR) is a model of inflammatory and arthritic pain similar to that of clinical gout. Nociception is induced by the intra-articular injection of uric acid into the right hind limb, inducing its dysfunction. Animals then receive analgesic drugs and the recovery of functionality over time is assessed as an expression of antinociception. We have examined the role of peripheral prostaglandins synthesized by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in inflammatory pain using the PIFIR model. Rofecoxib (a selective COX-2 inhibitor) and SC-560 (a selective COX-1 inhibitor) both produced dose-dependent effects. When the inhibitors were administered before uric acid, they showed similar potency, but the antinociceptive efficacy of SC-560 was lower than rofecoxib; the best antinociceptive effects were obtained with the dose of 100 microg/articulation of each inhibitor (pre-treatment). In post-treatment (inhibitors administered after the uric acid), rofecoxib showed the least antinociceptive effect and SC-560 was more potent than rofecoxib. The inhibition of both COX-1 and COX-2 produced a more profound analgesic effect than the inhibition of either COX-1 or COX-2 alone. The present data support the idea that both COX isoforms contribute to the development and maintenance of local inflammatory nociception. Thus, it could be expected that inhibition of both COX-1 and COX-2 is required for non-steroidal anti-inflammatory drugs (NSAID)-induced antinociception in the rat. These findings suggest that the therapeutic effects of NSAIDs may involve, at least in part, inhibition of COX-1 and COX-2.     

Determinants of the short-term gastric damage caused by NSAIDs in man

BACKGROUND: The short-term gastric damage seen with non-steroidal anti-inflammatory drugs (NSAIDs) in man may involve inhibition of cyclooxygenase (COX-1) and COX-2 as well as the topical irritancy, which is dependant on the acidity (pKa) and/or lipophilicity (log P(7.4)). AIM: To study the quantitative relationship between NSAID-induced short-term gastric damage, their physicochemical properties and contrasting roles of COX-1 and COX-2 inhibition. METHODS: We identified studies that allowed a qualitative comparison of the gastric injury (Lanza scores) induced by NSAIDs with their pKa and log P(7.4). Damage was correlated with gastric COX inhibition and potency to inhibit COX-1 and 2 and their COX-2/COX-1 selectivity ratio. RESULTS: The gastric damage correlates significantly with pKa (r = -0.69; P < 0.01), log P (r = -0.58, P < 0.05) and potency of the NSAIDs to inhibit COX-1 (r = -0.61, P < 0.02), but not with COX-2 inhibition or COX-2/COX-1 selectivity. CONCLUSION: Against a background of COX-1 and COX-2 inhibition, the physicochemical properties of NSAID appear to play an important role in short-term gastric damage.     

Pharmacokinetics and pharmacodynamics of pentopril, a new angiotensin-converting-enzyme inhibitor in humans

In a single, ascending-dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero-order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125- and 250-mg doses, showed a dose proportional urinary recovery of 21% (+/- 5%) for pentopril and 40% (+/- 5%) for CGS 13934. In the multiple-dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half-lives (pentopril, less than 1 hr; CGS 13934, approximately 2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin-I (AI)-induced changes in blood pressure and plasma angiotensin-converting-enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10-500 mg). The pharmacodynamic half-life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI-induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half-maximal inhibition of 53 ng/mL.     

Covalent binding of radioactivity from [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706, to the arterial elastin of rats.

Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor that has been withdrawn from the market because of an increased risk of cardiovascular (CV) events. With a special focus on the arteries, the distribution profiles of radioactivity in rats orally administered [14C]rofecoxib were investigated in comparison with two other COX-2 inhibitors, [14C]celecoxib and [14C]CS-706 (2-(4-ethoxyphenyl)-4-methyl 1-(4-sulfamoylphenyl)-1H-pyrrole), a novel selective COX-2 inhibitor. Whole-body autoradioluminography and quantitative determination of the tissue concentrations showed that considerable radioactivity is retained by and accumulated in the thoracic aorta of rats after oral administration of [14C]rofecoxib, but not [14C]celecoxib or [14C]CS-706. Acid, organic solvent, and proteolytic enzyme treatments of aorta retaining high levels of radioactivity from [14C]rofecoxib demonstrated that most of the radioactivity is covalently bound to elastin. In agreement with this result, the radioactivity was found to be highly localized on the elastic fibers in the aorta by microautoradiography. The retention of radioactivity on the elastic fibers was also observed in the aortic arch and the coronary artery. These findings indicate that [14C]rofecoxib and/or its metabolite(s) are covalently bound to elastin in the arteries. These data are consistent with the suggestion of modified arterial elasticity leading to an increased risk of CV events after long-term treatment with rofecoxib.     

A Randomized,Double-Blind,Placebo- and Active-Controlled,Escalating Single-Dose Study to Evaluate the Safety,Tolerability, Pharmacokinetic,and Pharmacodynamic Profiles of Subcutaneous Eflapegrastim in Healthy Japanese and Caucasian Subjects

BackgroundEflapegrastim (Rolontis^®) is a novel long‐acting pegylated recombinant human granulocyte colony-stimulating factor (G-CSF). Eflapegrastim has been developed to reduce the duration and incidence of chemotherapy-induced neutropenia in cancer patients using patient-friendly, less-frequent administration.ObjectiveThis phase I study aimed to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and immunogenicity of eflapegrastim following a single subcutaneous administration to healthy Japanese and Caucasian subjects.MethodsA randomized, double-blind, placebo- and active-controlled, dose-escalation study was conducted in healthy Japanese and Caucasian subjects. Eligible subjects randomly received a single subcutaneous administration of eflapegrastim (1.1, 3.3, 10, 45, 135, and 270 μg/kg), pegfilgrastim 6 mg, or placebo in a ratio of 6:2:2 (Cohorts 1–2, Caucasian subjects only) or 12:2:2 (Cohorts 3–6, Japanese and Caucasian subjects). Safety and tolerability were assessed throughout the study. Serial blood samples were collected predose and up to day 22 postdose for PK and PD analyses. PK assessments were performed in the 45, 135, and 270 µg/kg dose groups. Antidrug antibodies to eflapegrastim were determined at baseline up to day 42 after the first dose for immunogenicity.ResultsA total of 84 subjects (42 males and 42 females) were enrolled, and 78 (31 Japanese and 47 Caucasian subjects) completed the study as planned. Japanese and Caucasian subjects showed similar PK and PD profiles. In the 45, 135, and 270 µg/kg dose groups, the maximum serum concentration (C_max) of eflapegrastim exhibited a dose-proportional increase, whereas its exposure increased greater than dose proportional in both ethnic groups. The mean area under the effect-time curve (AUEC_last) and maximum serum concentration of both absolute neutrophil count (ANC_max) and CD34⁺ cell count (CD34⁺_max) increased in a dose-dependent manner. There were no significant adverse events attributable to eflapegrastim or pegfilgrastim in both Japanese and Caucasian subjects. No neutralizing antibodies against G‐CSF were detected.ConclusionsEflapegrastim was safe and well tolerated at doses up to 270 μg/kg in healthy Japanese and Caucasian subjects. In both ethnic groups, eflapegrastim showed dose-dependent PK and the exposure to eflapegrastim was positively correlated with ANC and CD34⁺ cell count. The comparable PK and PD profiles of eflapegrastim in Japanese and Caucasian subjects may indicate the same dosage regimen is acceptable.Clinical Trial RegistrationClinicalTrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01037543","term_id":"NCT01037543"}}NCT01037543 (23 December 2009).     

关苍术超临界提取物对乙醇致大鼠胃黏膜损伤保护作用的研究

目的:研究关苍术超临界提取物(GCT)对乙醇致大鼠胃黏膜损伤的保护作用。方法:40只Wistar大鼠均分成5组,即空白对照(等容蒸馏水)、模型(等容蒸馏水)、铝碳酸镁(0.37g.kg-1)和GCT高、低剂量(0.70、0.35g.kg-1)组。ig给药,每天1次,连续5d,末次给药30min后ig无水乙醇(0.5mL.100g-1)复制急性胃黏膜损伤模型,观察胃黏膜损伤面积,测定胃组织中丙二醛(MDA)、一氧化氮(NO)含量和超氧化物歧化酶(SOD)、髓过氧化物酶(MPO)、一氧化氮合成酶(NOS)活性及环氧化物酶2(COX-2)蛋白表达水平。结果:高、低剂量GCT能显著抑制乙醇引起的大鼠胃黏膜损伤及胃组织中MDA含量的增加和MPO活性的升高,抑制SOD活性的减弱、NO含量和NOS活性的降低,并抑制COX-2蛋白的表达。结论:GCT能拮抗乙醇引起的胃黏膜损伤,其机制可能与通过抑制氧自由基产生、维持胃黏膜中NO正常水平、下调COX-2表达有关。     

Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors

A new class of selective cyclooxygenase-2 (COX-2) inhibitors has been identified by high throughput screening. Structurally distinct from previously described selective COX-2 inhibitors, these benzopyrans contain a carboxylic acid function and CF3 functionality. The compound SC-75,416 is a representative of this class. A range if in vitro and in vivo tests were employed to characterize its potency and selectivity. Using human recombinant enzymes, this compound displays a concentration that provides 50% inhibition (IC50) of 0.25 microM for COX-2 and 49.6 microM for COX-1. A mutation of the side pocket residues in COX-2 to COX-1 had little effect on potency suggesting that these inhibitors bind in a unique manner in COX-2 distinct from COX-2 inhibiting diaryl heterocycles. Using rheumatoid arthritic synovial cells stimulated with interleukin-1beta (IL-1beta) and washed platelets the compound displayed IC50 of 3 nM and 400 nM respectively. Potency and selectivity was maintained but predictably right shifted in whole blood with IC50 of 1.4 microM for lipopolysaccharide (LPS) stimulated induction of COX-2 and >200 microM for inhibition of platelet thromboxane production. SC-75,416 is 89% bioavailable and its in vivo half life is sufficient for once a day dosing. In the rat air pouch model of inflammation, the compound inhibited PGE2 production with an effective dose that provides 50% inhibition (ED50) of 0.4 mg/kg, while sparing gastric prostaglandin E2 (PGE2) production with an ED50 of 26.5 mg/kg. In a model of acute inflammation and pain caused by carrageenan injection into the rat paw, the compound reduced edema and hyperalgesia with ED50s of 2.7 and 4 mg/kg respectively. In a chronic model of arthritis the compound demonstrated an ED50 of 0.081 mg/kg and an ED(80) of 0.38 mg/kg. In a model of neuropathic pain, SC-75,416 had good efficacy. This compound's unique chemical structure and effect on COX enzyme binding and activity as well as its potency and selectivity may prove useful in treating pain and inflammation.     

Similarity of insulin detemir pharmacokinetics, safety, and tolerability profiles in healthy caucasian and Japanese american subjects

The objective of this study was to compare the pharmacokinetics of insulin detemir in three ascending doses in healthy Japanese and Caucasian subjects. This was an open-label, single-center, parallel-group design evaluating 30 subjects (15 Japanese and 15 Caucasians). Subjects received a total of three subcutaneous injections (one injection per visit) of insulin detemir (0.19, 0.38, 0.75 U/kg [1 U = 24 nmol]) in ascending order. Following drug administration, subjects received intravenous glucose in 0.5-mg/kg/min increments every 30 minutes, followed by a constant rate of 2.0 mg/kg/min for up to 12 hours. For pharmacokinetic evaluations, serial blood sampling was performed over a period of 30 hours after dosing. Of the subjects, 36 were enrolled, and 30 completed the study. There was a linear dose-response relationship between the three ascending insulin detemir doses and serum insulin detemir AUC values for both the Japanese and Caucasian subjects. The two dose-response regression lines had equivalent slopes but slightly different intercepts (although not statistically significant). This difference may be due to variation in AUC, body weight differences, or chance. Six subjects discontinued the study, 2 as a result of adverse events (blood draw-related ecchymosis and hypoglycemia). The most frequent treatment-emergent adverse events (TEAE) were headache, dizziness, and reactions related to blood draws/infusion sites. All TEAEs were mild to moderate in severity. The results show that an increase in insulin detemir dose will result in a similar increase in insulin detemir concentration in the two ethnic groups. Therefore, therapeutic dosing of insulin detemir is expected to be similar in both ethnic groups, with no special dose adjustment or algorithm based on race. Insulin detemir at 0.19, 0.38, and 0.75 U/kg was generally well tolerated in both Japanese and Caucasian subjects.     

A protective role for cyclooxygenase-2 in drug-induced liver injury in mice.

Despite the utility of cyclooxygenase (COX) inhibition as an antiinflammatory strategy, prostaglandin (PG) products of COX-1 and -2 provide important regulatory functions in some pathophysiological states. Scattered reports suggest that COX inhibition may also promote adverse drug events. Here we demonstrate a protective role for endogenous COX-derived products in a murine model of acetaminophen (APAP)-induced acute liver injury. A single hepatotoxic dose caused the selective induction of COX-2 mRNA and increased PGD2 and PGE2 levels within the livers of COX(+/+) male mice suggesting a role for COX-2 in this model of liver injury. APAP-induced hepatotoxicity and lethality were markedly greater in COX-2(-/-) and (-/+) mice in which normal PG responsiveness is altered. The significantly increased toxicity linked to COX-2 deficiency could be mimicked using the selective COX-2 inhibitory drug, celecoxib, in COX(+/+) mice and was not due to alterations in drug-protein adduct formation, a surrogate for bioactivation and toxicity. Microarray analyses indicated that increased injury associated with COX-2 deficiency coincided, most notably, with a profoundly impaired induction of heat shock proteins in COX-2(-/+) mice suggesting that PGs may act as critical endogenous stress signals following drug insult. These findings suggest that COX-2-derived mediators serve an important hepato-protective function and that COX inhibition may contribute to the risk of drug-induced liver injury, possibly through both nonimmunological and immunological pathways.     

Population Pharmacodynamic Modelling of Aspirin- and Ibuprofen-Induced Inhibition of Platelet Aggregation in Healthy Subjects

OBJECTIVE: The objective of this study was to develop a mechanism-based pharmacodynamic model that characterizes the antiplatelet effects of aspirin (acetylsalicylic acid) and ibuprofen alone and in combination. METHODS: Ten healthy volunteers were enrolled in a single-blinded, randomized, three-way crossover study. Treatments consisted of single doses of oral aspirin (325 mg) and ibuprofen (400 mg) and concomitant administration of aspirin (325 mg) and ibuprofen (400 mg). Ex vivo whole blood platelet aggregation induced by collagen (1 microg/mL) or arachidonic acid (0.5 mmol/L) was measured by impedance aggregometry. Model development and population parameter estimation were performed using nonlinear mixed-effects modelling implemented in NONMEM. RESULTS: Relatively complete inhibition of platelet aggregation was achieved following aspirin treatment (approximately 77% inhibition within 2 hours), and return to baseline values occurred within 72-96 hours after dosing. In contrast, treatment with ibuprofen alone or in combination with aspirin produced transient inhibition of platelet aggregation, with complete recovery observed in 6-8 hours. The final pharmacodynamic model was based on the turnover of cyclo-oxygenase-1 (COX-1) enzyme, and incorporated irreversible inhibition by aspirin and reversible binding and antiplatelet effects of ibuprofen. The temporal response profiles from all three study arms were well described by the final model, and the parameters were estimated with good precision. The apparent turnover rate constant for COX-1 (kout) and the irreversible inhibition rate constant for aspirin (K) were estimated to be 0.0209 h(-1) and 0.152 (mg/L)(-1).h(-1), with interindividual variability of 30.6% and 26.2%, respectively. Simulations were used to evaluate the influence of clinically relevant ibuprofen regimens on the antiplatelet effect of aspirin, confirming clinical reports that the antiplatelet effect of aspirin would be blocked when multiple daily doses of ibuprofen are given, even if taken after aspirin administration. CONCLUSIONS: A mechanism-based pharmacodynamic model has been developed that characterizes the antiplatelet effects of aspirin and ibuprofen, alone and concomitantly, and predicts a significant inhibition of aspirin antiplatelet effects in the presence of a typical ibuprofen dosing regimen.     

Role of cyclooxygenase isoforms in gastric mucosal defense and ulcer healing

The rationale for the development of selective inhibitors of cyclooxygenase-2 (COX-2) was the proposal that this enzyme plays an important role in inflammation but does not contribute to the resistance of the gastrointestinal mucosa against injury. However, studies from several groups have established that both COX-1 and COX-2 have important functions in the maintenance of gastrointestinal mucosal integrity. Thus, in the normal rat stomach lesions only develop when both COX-1 and COX-2 are inhibited. On the other hand, in specific pathophysiological situations the isolated inhibition of either COX-1 or COX-2 without simultaneous suppression of the other COX isoenzyme is ulcerogenic. Furthermore, COX-2 plays an important role in the healing of gastric ulcers and inhibition of COX-2 delays ulcer healing. From these findings the initial concept that only inhibition of COX-1 interferes with gastrointestinal defense has to be re-evaluated.