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Aims: HTL0018318 is a selective M 1 receptor partial agonist currently under development for the symptomatic treatment of cognitive and behavioural symptoms in Alzheimer's disease and other dementias. We investigated safety, tolerability, pharmacokinetics and exploratory pharmacodynamics (PD) of HTL0018318 following single ascending doses., Methods: This randomized, double-blind, placebo-controlled study in 40 healthy younger adult and 57 healthy elderly subjects, investigated oral doses of 1-35 mg HTL0018318. Pharmacodynamic assessments were performed using a battery of neurocognitive tasks and electrophysiological measurements. Cerebrospinal fluid concentrations of HTL0018318 and food effects on pharmacokinetics of HTL0018318 were investigated in an open label and partial cross-over design in 14 healthy subjects., Results: Pharmacokinetics of HTL0018318 were well-characterized showing dose proportional increases in exposure from 1-35 mg. Single doses of HTL0018318 were associated with mild dose-related adverse events of low incidence in both younger adult and elderly subjects. The most frequently reported cholinergic AEs included hyperhidrosis and increases in blood pressure up to 10.3 mmHg in younger adults (95% CI [4.2-16.3], 35-mg dose) and up to 11.9 mmHg in elderly subjects (95% CI [4.9-18.9], 15-mg dose). There were no statistically significant effects on cognitive function but the study was not powered to detect small to moderate effect sizes of clinical relevance., Conclusion: HTL0018318 showed well-characterized pharmacokinetics and following single doses were generally well tolerated in the dose range studied. These provide encouraging data in support of the development for HTL0018318 for Alzheimer's disease and other dementias., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aim: To assess persistence with subcutaneous (SC) tumour necrosis factor (TNF) inhibitors as well as the impact of persistence on healthcare resource utilization (HCRU) and costs in patients with chronic inflammatory joint diseases., Methods: In this cohort study using population-based French claims data (from 2011 to 2014), we measured persistence with SC TNF inhibitors within 12 months (M0-12) following treatment initiation in treatment-naïve and treatment-experienced users (divided into three cohorts: rheumatoid arthritis [RA], ankylosing spondylitis [AS] and psoriatic arthritis [PsA]). Persistent patients were propensity score matched to nonpersistent patients at M12. The impact of persistence status on HCRU and costs was assessed during M12-24., Results: Of treatment-naïve (n = 3,804) and treatment-experienced (n = 2,279) users, only 56.1% and 46.8% were persistent at M12, respectively. Nonpersistent patients had more outpatient visits, computerized tomography scans, spine or joint magnetic resonance imaging procedures and disease-related hospitalizations, while persistent patients had more rheumatologist visits. Nonpersistent patients had lower drug costs but higher nondrug-related healthcare and hospitalization costs than persistent patients. In AS and PsA, overall healthcare costs were similar in persistent and nonpersistent patients. In RA, overall healthcare costs were lower in persistent patients (15,753€ vs 17,590€ in treatment-naïve and 17,622€ vs 21,177€ in treatment-experienced)., Conclusion: Persistence with SC TNF inhibitors within first 12 months following treatment initiation was low in both treatment-naïve and treatment-experienced patients. Differences were observed in distribution of costs between persistent and nonpersistent patients, showing that nonpersistence with SC TNF inhibitors can lead to increased HCRU and higher costs., (© 2020 The British Pharmacological Society.)

Aim: To describe the characteristics of inpatients with diabetes in a tertiary hospital in China using an electronic medical record (EMR)-based database., Methods: We identified the medical records of all patients with diabetes from nonpediatric departments of West China Hospital, Sichuan University (from February 2009 to December 2013), and extracted information on demographic, diagnosis, discharge outcome, department of discharge, laboratory test, and prescription from the EMR system. The quality of the database was assessed by analyzing missing data and extreme data and by reviewing the International Classification of Diseases 10th Revision (ICD-10) coding., Results: Among 683,267 discharged patients, 56,784 (8.3%) patients diagnosed with diabetes were identified from all departments. Among the patients with diabetes, the average age was 63.5 ± 13.1 years and the overall death in hospital was 2.2%. Laboratory test results were highly completed in our database with no extreme or discrepant value identified. Anthropometric parameters were of a relatively low quality as 62.2% body-mass index data were missing. HbA1c levels at admission were available for 36.7% patients with diabetes. The ICD-10 coding of the diagnosis of diabetes was accurate in 88.6% records reviewed. Dyslipidemia (76.5%), hypertension (51.3%), chronic kidney disease (22.1%), and hyperuricemia (16.2%) were the most commonly presented comorbidities among inpatients with diabetes., Conclusions: Our study indicated a wide distribution of diabetes throughout the inpatients in a tertiary hospital in southwest China. This EMR-based database of diabetes could be potentially useful in further investigations., (© 2018 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

Objective: To evaluate a modified Finnish Diabetes Risk Score (FINDRISC) for predicting the risk of incident diabetes among white and black middle-aged participants from the Atherosclerosis Risk in Communities (ARIC) study., Research Design and Methods: We assessed 9754 ARIC cohort participants who were free of diabetes at baseline. Logistic regression and receiver operator characteristic (ROC) curves were used to evaluate a modified FINDRISC for predicting incident diabetes after 9 years of follow-up, overall and by race/gender group. The modified FINDRISC used comprised age, body mass index, waist circumference, blood pressure medication and family history., Results: The mean FINDRISC (range, 2 [lowest risk] to 17 [highest risk]) for black women was higher (9.9 ± 3.6) than that for black men (7.6 ± 3.9), white women (8.0 ± 3.6) and white men (7.6 ± 3.5). The incidence of diabetes increased generally across deciles of FINDRISC for all 4 race/gender groups. ROC curve statistics for the FINDRISC showed the highest area under the curve for white women (0.77) and the lowest for black men (0.70)., Conclusions: We used a modified FINDRISC to predict the 9-year risk of incident diabetes in a biracial US population. The modified risk score can be useful for early screening of incident diabetes in biracial populations, which may be helpful for early interventions to delay or prevent diabetes., (© 2017 John Wiley & Sons Ltd.)

Aims: To compare diabetes-associated secondary healthcare utilization in patients with type 2 diabetes (T2DM) prescribed sulphonylureas (SUs) versus other oral antihyperglycaemic agents (OHAs) as an add-on to metformin monotherapy (metformin + SU vs metformin + OHA)., Methods: This retrospective cohort study used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. Adults with T2DM initiated on metformin + SU or metformin + OHA from April 2003 to March 2012 were identified. Patients were matched using propensity scores. Diabetes-associated secondary healthcare visits were counted from >6 months post-initiation of dual therapy until treatment change or end of follow-up. Outcomes were calculated as rate ratios, adjusted for over-dispersion using negative binomial regression and propensity score for covariates., Results: After propensity score matching, 1704 patients were included in each cohort. For the primary objective (diabetes-associated inpatient and outpatient visits combined), the metformin + SU cohort had a directionally higher rate of diabetes-associated secondary healthcare utilization than the metformin + OHA cohort [adjusted rate ratio 1.12, 95% confidence interval (CI) 0.97-1.29]. For the secondary outcomes, the adjusted rate ratio was 1.38 (95% CI 0.95-2.00) for inpatient admissions and 1.10 (95% CI 0.95-1.28) for outpatient visits. Macrovascular complications, accounting for 77.2% of inpatient admissions, occurred at a statistically significantly higher rate in the metformin + SU cohort than in the metformin + OHA cohort (adjusted rate ratio 1.77, 95% CI 1.15-2.71)., Conclusions: This study found a statistically significant higher rate of inpatient admissions for macrovascular complications and cardiology outpatient visits and, overall, a directionally higher rate of secondary healthcare utilization for patients prescribed metformin + SU than for those prescribed metformin + OHA. This adds to the evidence that long-term and health economic outcomes should be considered in treatment decisions for patients with type 2 diabetes., (© 2015 John Wiley & Sons Ltd.)

Virus filtration (VF) is a key step in an overall viral clearance process since it has been demonstrated to effectively clear a wide range of mammalian viruses with a log reduction value (LRV) > 4. The potential to achieve higher LRV from virus retentive filters has historically been examined using bacteriophage surrogates, which commonly demonstrated a potential of > 9 LRV when using high titer spikes (e.g. 10(10) PFU/mL). However, as the filter loading increases, one typically experiences significant decreases in performance and LRV. The 9 LRV value is markedly higher than the current expected range of 4-5 LRV when utilizing mammalian retroviruses on virus removal filters (Miesegaes et al., Dev Biol (Basel) 2010;133:3-101). Recent values have been reported in the literature (Stuckey et al., Biotech Progr 2014;30:79-85) of LRV in excess of 6 for PPV and XMuLV although this result appears to be atypical. LRV for VF with therapeutic proteins could be limited by several factors including process limits (flux decay, load matrix), virus spike level and the analytical methods used for virus detection (i.e. the Limits of Quantitation), as well as the virus spike quality. Research was conducted using the Xenotropic-Murine Leukemia Virus (XMuLV) for its direct relevance to the most commonly cited document, the International Conference of Harmonization (ICH) Q5A (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Geneva, Switzerland, 1999) for viral safety evaluations. A unique aspect of this work is the independent evaluation of the impact of retrovirus quality and virus spike level on VF performance and LRV. The VF studies used XMuLV preparations purified by either ultracentrifugation (Ultra 1) or by chromatographic processes that yielded a more highly purified virus stock (Ultra 2). Two monoclonal antibodies (Mabs) with markedly different filtration characteristics and with similar levels of aggregate (<1.5%) were evaluated with the Ultra 1 and Ultra 2 virus preparations utilizing the Planova 20 N, a small virus removal filter. Impurities in the virus preparation ultimately limited filter loading as measured by determining the volumetric loading condition where 75% flux decay is observed versus initial conditions (V75). This observation occurred with both Mabs with the difference in virus purity more pronounced when very high spike levels were used (>5 vol/vol %). Significant differences were seen for the process performance over a number of lots of the less-pure Ultra 1 virus preparations. Experiments utilizing a developmental lot of the chromatographic purified XMuLV (Ultra 2 Development lot) that had elevated levels of host cell residuals (vs. the final Ultra 2 preparations) suggest that these contaminant residuals can impact virus filter fouling, even if the virus prep is essentially monodisperse. Process studies utilizing an Ultra 2 virus with substantially less host cell residuals and highly monodispersed virus particles demonstrated superior performance and an LRV in excess of 7.7 log10 . A model was constructed demonstrating the linear dependence of filtration flux versus filter loading which can be used to predict the V75 for a range of virus spike levels conditions using this highly purified virus. Fine tuning the virus spike level with this model can ultimately maximize the LRV for the virus filter step, essentially adding the LRV equivalent of another process step (i.e. protein A or CEX chromatography)., (© 2014 American Institute of Chemical Engineers.)

Aims: To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916., Methods: Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [(13)C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [(13)C4]cortisone., Results: Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11β-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK-0916 was generally well tolerated., Conclusions: These findings indicate that 11β-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated., (© 2013 Merck, Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,. Whitehouse Station, NJ, USA. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

Antihyperglycaemic therapy on bone was evaluated in the ovariectomized (OVX), non-diabetic adult rat. Animals were treated daily for 12 weeks with various doses of sitagliptin, pioglitazone, rosiglitazone, combinations of sitagliptin with pioglitazone or vehicle alone. Sitagliptin target engagement was confirmed by assessing inhibition of plasma dipeptidyl peptidase-4 (DPP-4) and oral glucose tolerance. Parameters related to bone health were evaluated in femur and vertebrae by dual-energy X-ray absorptiometry and histomorphometry. Bone mineral density (BMD) generally did not differ significantly between OVX-sitagliptin-treated animals and OVX-vehicle controls. In lumbar vertebrae, however, there was significantly less BMD loss with increasing sitagliptin dose. Thiazolidinedione (TZD) treatment generally resulted in lower BMD; OVX-TZD-treated (but not OVX-sitagliptin-treated) animals also had lessened cortical thickness in central femur and profoundly greater bone marrow adiposity in lumbar vertebrae. These findings support prior findings with TZDs and suggest a neutral or beneficial impact of DPP-4 inhibition on bone health., (© 2013 John Wiley & Sons Ltd.)

Aims: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans., Methods: Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women)., Results: Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ∼40-80 h. The area under the curve0-24 hours (AUC(0-24 h)), concentration at 24 hours (C(24 h)) and maximum concentration (C(max,overal)) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ∼100% increases in AUC(0-24 h), C(max,day1), C(max,overall) and C(24 h) relative to the fasted state, while administration with a low-fat meal led to a ∼30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ≥5 mg and at 168 h postdose for ≥10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ∼80% maximal reduction., Conclusions: Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing., (© 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Aim: To examine the impact of diabetes duration, chronic pancreatitis and other factors on pancreatic cancer risk., Methods: This retrospective cohort study using the UK General Practice Research Database compared pancreatic cancer incidence and risk in patients with type 2 diabetes mellitus (T2DM) versus patients without diabetes. Multivariate Cox regression adjusting for age, sex, history of chronic pancreatitis, gallbladder disease, obesity, smoking and alcohol use and Charlson comorbidity index was used to estimate hazard ratio (HR) [95% confidence interval, CI]. Analyses were repeated using various time windows for diabetes duration., Results: A total of 1903 incident pancreatic cancers were identified, 436 in patients with T2DM (78.76 per 100 000 person-years [95% CI: 71.54, 86.51]) and 1467 in patients without diabetes (11.46 per 100 000 person-years [10.88, 12.06]). Pancreatic cancer risk was significant for T2DM (adjusted HR 1.80 [1.52, 2.14]), increasing age, history of chronic pancreatitis and tobacco use. For patients with chronic pancreatitis and T2DM, the adjusted HR was 12.12 [6.02, 24.40]. Incidence was highest in patients with ≥5 year duration of T2DM. In patient populations with duration of T2DM ranging from ≥1 to ≥5 years, adjusted HRs remained significant but point estimates attenuated slightly with longer duration of T2DM., Conclusions: Patients with T2DM had an 80% increased risk of pancreatic cancer versus patients without diabetes. Patients with T2DM and chronic pancreatitis were 12 times more likely to develop pancreatic cancer., (© 2012 Blackwell Publishing Ltd.)

Aim: To compare the time from initial diagnosis to initiation with oral antihyperglycaemic treatment in younger versus older patients with type 2 diabetes, and to evaluate factors associated with initiating treatment., Methods: This was a retrospective US cohort study with a 2-year follow-up period after diagnosis of type 2 diabetes. Using the General Electric Healthcare's Clinical Data Services electronic medical record database, eligible patients included those aged ≥30 years at initial diagnosis of type 2 diabetes between January 2003 and December 2005. In the 2-year period following diagnosis, the time to the first prescription of an oral antihyperglycaemic agent was compared between younger (30-64 years) and older (≥65 years) patients. Factors associated with time to treatment with an oral antihyperglycaemic agent were examined using Cox proportional hazards regression., Results: Of the 10 743 patients with newly diagnosed type 2 diabetes, 43% were ≥65 years old. The mean age at diagnosis was 73 years for older patients and 52 years for younger patients. Compared to younger patients, a greater proportion of older patients had a baseline haemoglobin A1c (HbA1c) value <7% (38 vs. 32%; p < 0.001). In the 2-year follow-up period, a significantly greater proportion of younger patients (59%) received oral antihyperglycaemic treatment compared to older patients (44%; p < 0.001). The median time between diagnosis and initiating treatment with an oral antihyperglycaemic agent was 350 days for younger patients and >2 years for older patients. After adjusting for covariates, older patients had a greater risk of not receiving treatment with oral antihyperglycaemic therapy than younger patients [adjusted hazard ratio = 0.82 (95% confidence interval: 0.75, 0.90)]., Conclusions: In patients with newly diagnosed type 2 diabetes, the time to initiation of oral antihyperglycaemic therapy was significantly longer in older patients (≥65 years old) than younger patients (<65 years)., (© 2011 Blackwell Publishing Ltd.)

Aim: To examine the effect of sitagliptin and metformin, alone and in combination, on modelled parameters of β-cell function in patients with type 2 diabetes., Methods: The data used in the present analyses are from a 104-week study, which included a 24-week, placebo- and active controlled phase followed by a 30-week, active controlled, continuation phase and an additional 50-week, active controlled extension phase. Patients were randomised to one of six blinded treatments: sitagliptin 50 mg + metformin 1000 mg b.i.d., sitagliptin 50 mg + metformin 500 mg b.i.d., metformin 1000 mg b.i.d., metformin 500 mg b.i.d., sitagliptin 100 mg q.d. or placebo. Patients on placebo were switched in a blinded manner to metformin 1000 mg b.i.d. at week 24. Subsets of patients volunteered to undergo frequently sampled meal tolerance tests at baseline and at weeks 24, 54 and 104. β-cell responsivity was assessed with the C-peptide minimal model. The static component (Φ(s)) estimates the rate of insulin secretion related to above-basal glucose concentration. The dynamic component (Φ(d)) is related to the rate of change in glucose. The total index (Φ(total)) represents the overall response to a glycaemic stimulus and is calculated as a function of Φ(s) and Φ(d). Insulin sensitivity was estimated with the Matsuda index (ISI). The disposition index, which assesses insulin secretion relative to the prevailing insulin sensitivity, was calculated based on the Φ(total) and ISI., Results: At week 24, substantial reductions in postmeal glucose were observed with all active treatment groups relative to the placebo group. Φ(s), Φ(total) and the disposition index were significantly improved from baseline at week 24 with all active treatments relative to placebo. Generally larger effects were observed with the initial combination of sitagliptin and metformin relative to the monotherapy groups. When expressed as median percent change from baseline, Φ(s) increased from baseline by 137 and 177% in the low- and high-dose combination groups and by 85, 54, 73 and -9% in the high-dose metformin, low-dose metformin, sitagliptin monotherapy and placebo groups, respectively. At weeks 54 and 104, the combination treatment groups continued to demonstrate greater improvements in β-cell function relative to their respective monotherapy groups., Conclusions: After 24 weeks of therapy, relative to placebo, initial treatment with sitagliptin or metformin monotherapy improved β-cell function; moreover, initial combination therapy demonstrated larger improvements than the individual monotherapies. Improvements in β-cell function were found with treatments for up to 2 years., (© 2011 Blackwell Publishing Ltd.)

Aims: Supraphysiologic glucocorticoid activity is well established to cause impaired glucose tolerance and insulin resistance, yet no study has evaluated dose-dependent effects of low-dose prednisone during short-term oral administration., Methods: The objective of this study was to quantify the effects of daily 10 or 25 mg prednisone administration for one week on insulin sensitivity by employing a two-step hyperinsulinemic euglycemic glucose clamp (Step 1: insulin infusion = 20 mU/m²/min; Step 2: insulin infusion = 80 mU/m²/min) in healthy, lean males. The amount of glucose infused at steady-state to maintain stable blood glucose [90 mg/dl (4.95 mmol/l)] was used to calculate several indices of insulin sensitivity., Results: During Step 1 of the clamp, whole body glucose disposal (M) was reduced by 35% (p = 0.003) and M/I was reduced by 29% (p = 0.025) for 25 mg prednisone compared to placebo. No appreciable effect of 10 mg prednisone was observed. During Step 2, M was reduced by 33% (p = 0.001) and 15% (p = 0.006) for 25 and 10 mg prednisone compared to placebo; and M/I ratio was reduced by 31% (p < 0.001) and 13% (p = 0.026), respectively. The insulin sensitivity index, Si, calculated as the quotient of augmentation of M/I between Step 1 and 2, was reduced by 35.3% (p < 0.01) and 23.5% (p < 0.05) for 25 and 10 mg prednisone, respectively., Conclusion: Administration of relatively low pharmacological doses of prednisone for one week impaired insulin sensitivity in a dose-dependent manner in healthy males. These observed changes in insulin sensitivity are likely to be clinically relevant, especially in individuals predisposed to develop glucose intolerance., (© 2011 Blackwell Publishing Ltd.)

Aims: An integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time., Methods: Data (n= 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects., Results: Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg(-1) 3 min after rocuronium, sugammadex 4 mg kg(-1) during deep neuromuscular blockade and sugammadex 2 mg kg(-1) during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time., Conclusions: Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min., (© 2011 N.V. Organon, a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., U.S.A. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Aim: We examined the effects of the 11β-hydroxysteroid dehydrogenase type 1 (HSD1) inhibitor, MK-0916, on the multiple components of the metabolic syndrome (MetS) in patients with type 2 diabetes (T2DM) and MetS., Methods: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled study. Patients with T2DM (mean baseline A1C: 7.3%) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)-defined MetS were randomized 1 : 1 : 1 : 1 to 0.5, 2 or 6 mg/day MK-0916 or placebo. The primary efficacy endpoint was a change from baseline at week 12 in fasting plasma glucose (FPG). Secondary endpoints included glycosylated haemoglobin A(1c) (A1C), 2-h postprandial glucose (2-h PPG), body weight, waist circumference, blood pressure and lipid profile., Results: Treatment with MK-0916 had no significant effect relative to placebo on FPG at week 12. Compared to placebo, 6 mg MK-0916 produced a modest, significant (p = 0.049) reduction in A1C of 0.3% at week 12, but no significant difference was observed in 2-h PPG. Six milligram MK-0916 increased LDL-C relative to placebo by 10.4% (p = 0.041). Treatment with MK-0916 led to modest dose-dependent decreases in blood pressure and body weight. Overall, MK-0916 was generally well tolerated. MK-0916 produced mechanism-based activation of the hypothalamic-pituitary-adrenal axis, resulting in mean increases in adrenal androgen levels that remained within the normal range at all doses tested., Conclusions: Inhibition of HSD1 with MK-0916 was generally well tolerated in patients with T2DM and MetS. Although no significant improvement in FPG was observed with MK-0916 compared to placebo, modest improvements in A1C, body weight and blood pressure were observed., (© 2011 Blackwell Publishing Ltd.)

Objective: Rheumatoid arthritis (RA) is characterized by inflammation and joint destruction, with the degree of damage varying greatly among patients. Prediction of disease severity using known clinical and serologic risk factors is inaccurate. This study was undertaken to identify new serologic markers for RA severity using an in silico model of the rheumatic joint., Methods: An in silico model of a prototypical rheumatic joint was used to predict candidate markers associated with erosiveness. The following 4 markers were chosen for validation: tartrate-resistant acid phosphatase 5b (TRAP-5b), N-telopeptide of type I collagen (NTX), angiopoietin 2 (Ang-2), and CXCL13. Serum from 74 RA patients was used to study whether radiologic joint destruction (total erosion score and total Sharp/van der Heijde score [SHS]) after 4 years of disease was associated with serum levels at the time of diagnosis. Serum marker levels were determined using enzyme-linked immunosorbent assays. For confirmation, baseline serum levels were analyzed for an association with progression of joint damage over 7 years of followup in a cohort of 155 patients with early RA., Results: Comparison of high and low quartiles of erosion score and SHS at 4 years showed a difference in baseline serum CXCL13 level (P = 0.011 and P = 0.018, respectively). In the confirmation cohort, elevated baseline CXCL13 levels were associated with increased rates of joint destruction during 7 years of followup (P < 0.001 unadjusted and P ≤ 0.004 with adjustment for C-reactive protein level). Analyzing anti-CCP-2-positive and anti-CCP-2–negative RA separately yielded a significant result only in the anti-CCP-2-negative group (P ≤ 0.001)., Conclusion: Our findings indicate that CXCL13 is a novel serologic marker predictive of RA severity.This marker was identified with the help of an in silicomodel of the RA joint.

In the mammalian central nervous system, transporter-mediated reuptake may be critical for terminating the neurotransmitter action of D-serine at the strychnine insensitive glycine site of the NMDA receptor. The Na(+) independent amino acid transporter alanine-serine-cysteine transporter 1 (Asc-1) has been proposed to account for synaptosomal d-serine uptake by virtue of its high affinity for D-serine and widespread neuronal expression throughout the brain. Here, we sought to validate the contribution of Asc-1 to D-serine uptake in mouse brain synaptosomes using Asc-1 gene knockout (KO) mice. Total [(3)H]D-serine uptake in forebrain and cerebellar synaptosomes from Asc-1 knockout mice was reduced to 34 +/- 5% and 22 +/- 3% of that observed in wildtype (WT) mice, respectively. When the Na(+) dependent transport components were removed by omission of Na(+) ions in the assay buffer, D-serine uptake in knockout mice was reduced to 8 +/- 1% and 3 +/- 1% of that measured in wildtype mice in forebrain and cerebellum, respectively, suggesting Asc-1 plays a major role in the Na(+) independent transport of D-serine. Potency determination of D-serine uptake showed that Asc-1 mediated rapid high affinity Na(+) independent uptake with an IC(50) of 19 +/- 1 microm. The remaining uptake was mediated predominantly via a low affinity Na(+) dependent transporter with an IC(50) of 670 +/- 300 microm that we propose is the glial alanine-serine-cysteine transporter 2 (ASCT2) transporter. The results presented reveal that Asc-1 is the only high affinity D-serine transporter in the mouse CNS and is the predominant mechanism for D-serine reuptake.

Adult mouse subventricular zone (SVZ) neural progenitor cells (NPCs) retain the capacity to generate multiple lineages in vitro and in vivo. Thus far, the mechanisms involved in the regulation of these cells have not been well elucidated. We have carried out RNA profiling of adult SVZ cell cultures undergoing differentiation, to identify pathways that regulate progenitor cell proliferation and to define a set of transcripts that can be used as molecular tools in the drug discovery process. We carried out a stepwise stratification of the results to identify transcripts specifically enriched in NPCs and validated some of these using comparative literature analysis, quantitative polymerase chain reaction and immunological techniques. The results show a set of transcription factors, secreted molecules and plasma membrane markers that are differentially regulated during differentiation. Pathway analysis highlights alterations in insulin growth factor, Wnt and transforming growth factor beta signalling cascades. Further characterization of these components could provide greater insight into the mechanisms involved in the regulation of neurogenesis in the adult brain.

The majority of inhibitory neurotransmission in the brain is mediated by the gamma-aminobutyric acid (GABA) type A (GABA(A)) receptor. The anticonvulsant loreclezole largely acts by potentiating GABA(A) receptors containing beta2 and beta3 subunits. We used a genetically modified mouse containing a loreclezole-insensitive beta2 subunit (beta2N265S) to determine the role of this subunit in mediating the sedative and anticonvulsive effects of loreclezole. Sedation was assessed by measuring spontaneous locomotor activity and beam walking performance, and anticonvulsant efficacy was determined by pentylenetetrazole (PTZ) and amygdala kindling-induced seizures. The beta2N265S mice did not exhibit loreclezole-mediated sedation as shown by normal locomotor activity and beam walking performance. However, loreclezole also failed to provide significant protection against PTZ-induced seizures in the beta2N265S mice. Reduced efficacy against amygdala-kindled seizures, both acutely and over a 13-day chronic dosing study, was also observed in beta2N265S mice. These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors.

Aims: This study, conducted by the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI), was designed to determine the amount of Phase 1 activity in the UK in the period 1999-2000, the timelines involved for submissions to ethics committee and responses from ethics committees., Methods: A questionnaire was completed by AHIPPI members from pharmaceutical companies with in-house phase 1 units, by Clinical Research Organizations (CRO's) and by academic centres. A few responses were also vailable from organisations that were not AHPPI members. Results were rendered anonymous and grouped by category., Results: The response rate was > 98% and indicated that the vast majority of early drug research in humans is now CRO-based (82%). The total number of studies (as indicated by protocol numbers) was notably similar across the 2 years--629 in 1999 and 606 in 2000. Turnaround time for ethics committee review was a mean of 14 days., Conclusions: These data set important benchmarks for early-phase drug research in the UK where regulatory approval is not currently required. Furthermore, the information should be used as a guide if the competitive nature of such work in the UK is to be maintained as new national legislation is implemented following publication of the European Union (EU) Clinical Trials Directive.

Aims: 5-HT1B-receptor mediated vasoconstriction of cranial arteries is a potential mechanism by which 5-HT1B/1D-receptor agonists such as sumatriptan produce their antimigraine effects. 5-HT1B-receptors exist in other blood vessels which may give rise to unwanted vascular effects. Therefore we examined the distribution of 5-HT1B-receptor immunoreactivity (i.r.) in human blood vessels (including target and nontarget vessels) and confirmed the functionality of this receptor protein, by comparing the vasoconstrictor effects of sumatriptan and 5-HT (the endogenous ligand) in isolated vessels., Methods: Blood vessels (middle meningeal, pial, temporal and uterine arteries and saphenous veins) were obtained from surgical patients (with consent). Sections of the vessels were prepared for routine immunohistochemical studies using specific 5-HT1B- and 5-HT1D-receptor antibodies. For functional studies, ring segments of the vessels were mounted in organ baths for isometric tension recording., Results: 5-HT1B-receptor i.r. was detected on the smooth muscle layer in middle meningeal, pial and uterine arteries and in saphenous vein and sumatriptan produced contractions in these vessels with potency values (mean pEC50) of 7.00, 7.08, 6.44 and 6.61, respectively, the magnitude of contraction was greatest in the cranial arteries with Emax values of 100.7, 60.3, 23.0 and 35.9%, respectively (expressed as a percentage of the reference agonist 45 mm KCl). 5-HT1B-receptor i.r. was not detected in temporal artery and sumatriptan had no effect in this artery. 5-HT1D-receptor i.r. was not detected in any of the vessels studied., Conclusions: Sumatriptan can evoke vasoconstriction in antimigraine target vessels and also in nontarget vessels through an action at 5-HT1B-rcceptors. Sumatriptan acts preferentially to cause contraction in human cranial arteries compared with the other blood vessels we examined and this effect is likely to be shared by other drugs of this class.

Vasodilatation in the dura mater has been implicated in migraine pathogenesis. Anti-migraine triptan drugs block vasodilatation by binding to 5-HT1B/1D receptors localized on the peripheral sensory terminals and dural blood vessel smooth muscles. Previous studies suggest that calcitonin gene-related peptide (CGRP) released from Adelta-fibres plays a more important role than substance P (SP) released from C-fibres in inducing dural vasodilatation and that one of the antimigraine mechanisms of triptan drugs is inhibiting CGRP release. In the present study, the relationship between CGRP and 5-HT1B/1D receptors, and between CGRP and SP in the trigeminal ganglion neurons in rats was examined by double immunohistochemical staining. CGRP, 5-HT1B, 5-HT1D and SP-positive trigeminal ganglion neurons were all predominantly small and medium-sized. In the trigeminal ganglia, approximately 50% of CGRP-positive neurons were 5-HT1B positive. Similarly, approximately 55% of CGRP-positive neurons were 5-HT1D immunoreactive. Approximately 50% of CGRP-positive neurons were SP-positive, while 93% of SP-positive neurons were CGRP-positive, suggesting that nearly all SP-positive neurons also contain CGRP. The fibre types of the 5-HT1B- and 5-HT1D-positive neurons were further investigated with an antibody against the A-fibre marker 200-kDa neurofilaments (NF200). Approximately 46% of the 5-HT1B-positive and 43% of the 5-HT1D-positive trigeminal ganglion neurons were also NF200 positive, indicating that many A-fibre trigeminal neurons express 5-HT1B or 5-HT1D receptors. These results support the hypothesis that one important action of antimigraine drugs is the inhibition of CGRP release and that Adelta-fibres may play an important role in migraine pathogenesis.

Aims: Vasoconstriction in human coronary artery can be mediated via activation of both 5-HT2 and 5-HT1B-receptors. Coronary vasoconstriction is a rare, but potential adverse effect of the antimigraine drug sumatriptan. In order to investigate the receptor population involved we compared the vasoconstrictor effects of sumatriptan (a mixed 5-HT1B/1D-receptor agonist) with those of L-775, 606 (a selective 5-HT1D-receptor agonist) and 5-HT (the endogenous ligand) in human isolated coronary arteries., Methods: Coronary arteries were obtained from human hearts removed prior to transplant surgery. Several endothelium denuded ring segments (4 mm in length) were obtained from each artery and mounted for isometric tension recording. Each segment was first exposed to 45 mm KCl and then to 5-HT (1 nm-100 microm ). Concentration-effect curves to L-775,606 (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)p ipe razine) and sumatriptan were then performed in a consecutive and random manner. The response to repeated application of 5-HT was obtained in separate segments., Results: Twenty-five segments from seven different coronary arteries were studied. Concentration-effect curves were fitted to the data using nonlinear regression analysis. The maximum contraction for L-775,606 was significantly less than that for sumatriptan with Emax values (% relative to 45 mm KCl=100%) of 30.1+/-4.22 and 41.5+/-2.7, respectively. L-775,606 was significantly (30-fold) less potent than sumatriptan in causing contraction compared with sumatriptan (EC50 values were 6.0 microm and 0.2 microm, respectively). For comparison the Emax value for 5-HT was 77.2% and the EC50 value was 0.2 microm., Conclusions: The selective 5-HT1D-receptor agonist L-775,606 has less propensity towards vasoconstriction in human isolated coronary artery (endothelium-denuded) than was mixed 5-HT1B/1D-receptor agonist sumatriptan. The contractions produced were at concentrations where L-775,606 would be expected to occupy 5-HT1B-receptors.

Aims: P256 is a divalent antibody which aggregates human platelets by interaction with glycoprotein (GP) IIb/IIIa receptors. We investigated the effect of tirofiban, an antagonist of the GP IIb/IIIa receptor, on P256-mediated platelet aggregation., Methods: Responses to agonists were measured turbidometrically at 37 degrees C in stirred citrated platelet-rich plasma from venous blood samples from healthy human volunteers. Inhibitory effects were determined by comparison with aggregation to the same concentration of agonist in a vehicle treated sample., Results: Tirofiban inhibited a near maximally effective dose of P256 (10-7 mol l-1 ) with an IC50 of 9. 3x10-8 mol l-1. Tirofiban (10-7 mol l-1 ) inhibited responses to arachidonic acid, U46619 and P256 similarly, whereas aspirin (1. 1x10-4 mol l-1 ) inhibited arachidonic acid more effectively than P256 (P<0.007 by anova )., Conclusions: Tirofiban potently and selectively inhibits P256-stimulated aggregation of human platelets.

Aims: Sumatriptan is a 5-HT1B/1D-receptor agonist which also has affinity for 5-HT1F-receptors. The vasoconstrictor effects of sumatriptan are thought to be 5-HT1B-receptor mediated and these receptors have been shown to be expressed in human cranial blood vessels. However, in the same tissue mRNA coding for 5-HT1F-receptors has also been identified and this study addresses the possibility of whether 5-HT1F-receptor activation contributes to vasoconstriction., Methods: The ability of two selective 5-HT1B/1D-receptor antagonists (GR125,743 and GR127,935) with no affinity for 5-HT1F-receptors, to inhibit sumatriptan evoked contractions in human isolated middle meningeal artery was investigated. Using a series of 5-HT1B/1D-receptor agonists (sumatriptan, zolmitriptan, CP122,288, L-741,519 and L-741,604), some with high affinity for 5-HTIF-receptors and the non-selective 5-HT-receptor agonists 5-HT and 5-CT, we compared the vasoconstrictor potency of these drugs in human isolated middle meningeal artery with their affinities at cloned human 5-HT1B-, 5-HT1D-and 5-HT1F-receptors expressed in CHO cell lines., Results: GR125,743 antagonized sumatriptan evoked contractions in a competitive manner (apparent pA2 9.1) and GR127,935 antagonized sumatriptan-induced responses in a non-competitive manner (reducing the maximum contraction to 27%). There was a significant correlation between vasoconstrictor potency and 5-HT1B-receptor affinity (r=0.93, P=0.002) but not with 5-HT1D- or 5-HT1F-receptor affinity (r=0.74, P=0.06; r= 0.31, P= 0.49, respectively)., Conclusions: These experiments show that in human middle meningeal artery vasoconstriction to sumatriptan-like agents is 5-HT1B-receptor mediated with little if any contribution from 5-HT1F-receptor activation.

Aims: We compared the vasoconstrictor effects of 5-HT with those of the selective 5-HT1B/1D-receptor agonists sumatriptan and rizatriptan in human isolated cranial (middle meningeal) arteries. In addition selective 5-HT1B- or 5-HT1D-receptor antibodies were used in combination with semiquantitative immunohistochemical techniques to compare the levels of expression of these receptors in human middle meningeal and coronary arteries., Methods: Middle meningeal and coronary arteries were obtained (with consent) from either neurosurgical patients or donor hearts, respectively. Segments of middle meningeal artery were mounted in organ baths for isometric recording and cumulative concentration-effect curves to 5-HT, rizatriptan and sumatriptan were obtained. Frozen fresh sections of middle meningeal and coronary arteries were subjected to standard immunohistochemical techniques using specific 5-HT1B- or 5-HT1D-receptor primary antibodies and a radiolabelled secondary antibody. Data were subjected to analysis of variance (ANOVA) and nonlinear regression analysis., Results: 5-HT, rizatriptan and sumatriptan were potent vasoconstrictors in human isolated middle meningeal artery (EC50 values=32, 90 and 71 nM, respectively). A significantly higher level of 5-HT1B-receptor immunoreactivity was detected in middle meningeal artery compared with coronary artery (ANOVA, F=7.95, DF=1,4, P<0.05)., Conclusions: Rizatriptan and sumatriptan act selectively to cause vasoconstriction in human isolated middle meningeal artery and are 10-fold more potent than in human coronary artery. The higher level of expression of 5-HT1B-receptors in middle meningeal compared with coronary artery provides a pharmacological basis for the craniovascular selectively of both rizatriptan and sumatriptan.

1. Two studies were undertaken to develop a model of experimentally induced anxiety in normal volunteers based on cholecystokinin (CCK) receptor agonism/antagonism. 2. In Study 1 rapid intravenous injections of the CCK receptor subtype B (CCKB) agonist pentagastrin (0.15, 0.3 and 0.6 micrograms kg-1) were found to produce dose-related increases in subjective ratings of anxiety compared with placebo. 3. In Study 2 the effects of pre-treatment with two doses of the CCKB receptor antagonist L-365,260 (10 mg, 50 mg p.o.) on the anxiety induced by pentagastrin 0.3 micrograms kg-1 i.v. were investigated. Detailed measurements of blood pressure and pulse rate were also undertaken. Pentagastrin produced changes in blood pressure and pulse rate which had a similar time course to that observed for subjective anxiety ratings. L-365,260 reversed both the autonomic and anxiogenic effects of pentagastrin. 4. The pentagastrin model would appear to be a useful tool for investigating potential anxiolytics in normal volunteers.

1. A double-blind, placebo controlled study has been conducted to investigate the consequences of i.v. treatment with MK-467, a peripherally selective alpha 2-adrenoceptor antagonist in exercising healthy male subjects. In particular, the effects on blood pressure, heart rate, circulating catecholamines (noradrenaline (NA) and adrenaline (A)), insulin, glucose and free fatty acids (FFA) were determined. 2. Exercise produced increases in catecholamines, blood pressure and heart rate. FFA increased at the start of the exercise but then declined as exercise progressed. 3. MK-467 significantly increased NA, in a dose-dependent manner, before and during exercise without altering A. Blood pressure and heart rate were not affected by drug treatment. 4. The insulin and FFA response to exercise was significantly enhanced by MK-467 although glucose was unaltered by drug. 5. It is concluded that both pre- and post-junctional peripheral alpha 2-receptors play an important role in the metabolic response to exercise in man.

Objective: To quantify stromelysin and collagenase in synovial fluid (SF) from patients with rheumatoid arthritis (RA) or traumatic knee injury., Methods: Stromelysin and collagenase were measured in the SF of 33 patients with RA or posttraumatic knee injury, using specific double-antibody sandwich enzyme-linked immunosorbent assays. Stromelysin was fractionated from representative SF, and the molecular form was identified by immunoblot analysis., Results: The stromelysin concentration was approximately 20-fold higher than the collagenase concentration in the fluids from patients with RA and approximately 8-fold higher in the fluids from patients with traumatic injury. For both metalloproteinases, there was a higher enzyme concentration in RA SF than in the SF from patients with trauma (stromelysin 40.1 +/- 26 micrograms/ml [mean +/- SD] in RA SF, 8.5 +/- 15 micrograms/ml in trauma SF; collagenase 2.2 +/- 3.3 micrograms/ml in RA SF, 1.1 +/- 2.3 micrograms/ml in trauma SF). The majority of the stromelysin within the SF bound to reactive red-agarose and was identified as prostromelysin based on electrophoretic mobility and immunoblotting with monospecific antibodies., Conclusion: The finding of high levels of stromelysin in SF from patients with RA supports the proposal that this enzyme may play a role in the connective tissue degradation observed in this disease.

A multicentre, double-blind, randomized, placebo-controlled trial was undertaken to investigate the therapeutic efficacy of a nocturnal dose of famotidine 20 mg to reduce the 1 year relapse rate of recently healed gastric ulcers. Twenty investigators in eight countries randomized 202 patients with endoscopically confirmed healed gastric ulcers. Repeat endoscopies were performed at 6 and 12 months or for symptoms compatible with ulcer relapse. A per protocol analysis of cumulative life table relapse at 12 months showed that famotidine 20 mg was superior to placebo in reducing gastric ulcer relapse, 24 versus 50%, respectively (P less than 0.01). Both placebo and famotidine were well tolerated. Since nocturnal dosing with famotidine 20 mg is effective in preventing gastric ulcer relapse over a 1-year period and is well tolerated, it offers a therapeutic option for the long-term treatment of patients with gastric ulcer.

7-Chlorokynurenate (7-Cl KYNA) and 3-amino-1-hydroxypyrrolid-2-one (HA-966), two selective antagonists of the glycine site on the N-methyl-D-aspartate (NMDA) receptor, have been used to assess the involvement of this site in the neurodegeneration resulting from injection of excitotoxins in the rat brain. In the rat striatum, reductions in the enzymes choline acetyltransferase (CAT) and glutamate decarboxylase (GAD), occurring 7 days after a unilateral, intrastriatal injection of quinolinate (200 nmol), were prevented in a dose-dependent manner by intrastriatal administration of 7-Cl KYNA (10 - 50 nmol) and HA-966 (200 - 500 nmol) 1 h after the excitotoxin. In the rat hippocampus, degeneration of pyramidal and granule neurons caused by direct injection of quinolinate (60 nmol) was completely prevented by 7-Cl KYNA (50 nmol) and partially by HA-966 (500 nmol) injected intrahippocampally 1 h after the excitotoxin. In the rat striatum, 7-Cl KYNA (50 nmol) and HA-966 (500 nmol) also reduced neurotoxicity caused by intrastriatal injection of NMDA (200 nmol), but not that caused by the 'non-NMDA' receptor agonists DL-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) or kainate. The time course of protective effects of 7-Cl KYNA and HA-966 in the striatum was similar to that previously observed with the uncompetitive NMDA receptor antagonist MK-801, indicating that activation of the glycine site contributes to the delayed degeneration of neurons which occurs over the first 5 h following quinolinate injection. The neuroprotective effects of both 7-Cl KYNA and HA-966 in the rat striatum appear to be mediated via the glycine site on the NMDA receptor as they were completely reversed by D-serine, but not L-serine. These results indicate that activation of the glycine site is essential for the expression of the delayed degeneration of neurons resulting from intracerebral injection of an NMDA receptor agonist, a process which bears similarities to the delayed neurodegeneration which results from a period of cerebral ischaemia.

Various steroids precipitate from supercritical CO(2) as very small particles but still retain their crystallinity. This suggests that SCFE in this industry could be utilized as a size reduction method as an alternative to milling. The application of SCFE as a separation technique is demonstrated by the simultaneous extraction and reaction of mevinolin, a metabolite of the fungus Aspergillus terreus.

One hundred ninety-nine outpatients with pain following oral surgery were randomly assigned, on a double-blind basis, a single oral dose of diflunisal (500 or 1,000 mg), zomepirac sodium 100 mg, aspirin 650 mg, or placebo. Using a self-rating record, subjects rated their pain and its relief hourly for 12 hours after medication. Measures of total and peak analgesia were derived from these patients' subjective reports. Diflunisal (500 and 1,000 mg) and zomepirac were significantly superior to aspirin and placebo for every measure of total and peak analgesia. Based upon the first 4 hours of observation, aspirin was superior to placebo for every measure of analgesia. Diflunisal 500 and 1,000 mg were comparable to zomepirac in peak analgesia and significantly superior to zomepirac for all measures of total analgesia. The onset of analgesia was comparable for 1,000 mg diflunisal, zomepirac, and aspirin, but more rapid for these treatments than for 500 mg diflunisal. The duration of analgesia was 12 hours for diflunisal, 9 hours for zomepirac, and 3 hours for aspirin., (1983 Pharmacotherapy Publications Inc.)

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.

The effects of diflunisal, a nonacetylated difluorinated salicylate, on platelet function were compared with those of aspirin and placebo. In a randomized, double-blind trial, normal subjects were given diflunisal, 250, 500, or 1,000 mg twice daily; aspirin, 650 or 1,300 mg twice daily; or placebo for 8-day periods. Diflunisal, 250 mg, had no effect on platelet function, whereas 500 mg induced minimal inhibition of collagen-induced release of platelet serotonin, and 1,000 mg inhibited platelet malondialdehyde production, moderately prolonged template bleeding times (p = NS), and increased fecal blood loss (p < 0.05). In contrast, aspirin, 650 mg, markedly inhibited collagen-induced platelet aggregation and serotonin release, and 1,300 mg prolonged bleeding time (p < 0.01) and increased fecal blood loss (p < 0.01). The effects of aspirin lasted for up to 5 days, whereas changes induced by diflunisal had returned to baseline 24 hours after the drug was discontinued. We conclude that in doses in the same range as those of aspirin diflunisal inhibits platelet function less., (1983 Pharmacotherapy Publications Inc.)

Famotidine now presents physicians in the USA and many European countries with a third option when considering H2-antagonist therapy. A dose of 40 mg in the evening decreases nocturnal gastric acidity for 10-12 hours, leaving daytime-stimulated acidity virtually unaffected. This single evening dosage regimen produces effective healing of gastric and duodenal ulceration; maintenance of healing can then be achieved satisfactorily with 20 mg in the evening. In extensive clinical studies, the adverse effect profile of famotidine is similar to placebo. Famotidine has no known drug interactions and there are no identified mechanisms by which it might be expected to produce them. Circulating plasma hormone concentrations in man are not affected by famotidine and no antiandrogenic properties have been observed in animal studies. Future potential uses of famotidine may include the treatment of haemorrhage from peptic ulcers and the healing of oesophageal ulceration.

The analgesic efficacy of single 500 and 1,000 mg doses of diflunisal, a new nonsteroidal antiinflammatory analgesic, was compared in a double-blind study with acetaminophen 600 mg, the combination of acetaminophen 600 mg with codeine 60 mg, and placebo in 132 inpatients with postoperative pain. Using a self-rating record, patients rated their pain and its relief hourly for up to 12 hours after medication. Diflunisal 500 and 1,000 mg were significantly superior to placebo for every measure of total and peak analgesia, and a significant analgesic effect persisted for 8 hours. Acetaminophen alone and the acetaminophen-codeine combination were significantly superior to placebo for most measures of analgesia, and their effects were significant for 4 and 5 hours respectively. Differences among the active medications were not statistically significant for measures of total or peak analgesia., (1983 Pharmacotherapy Publications Inc.)

In comprehensive clinical studies, diflunisal - a new nonsteroidal antiinflammatory drug with a long duration of action - was shown to be highly effective and generally well tolerated in the short- and long-term treatment of the pain of osteoarthritis. In double-blind comparison studies, diflunisal was comparable in efficacy to aspirin and better tolerated. In a separate study with ibuprofen, 800 to 1,200 mg daily (manufacturer's present recommended dose, 900 to 2,400 mg daily), diflunisal, 500 to 750 mg daily, was more effective and comparable in tolerability. Diflunisal had a longer duration of action, requiring only twice-a-day dosage., (1983 Pharmacotherapy Publications Inc.)

Diflunisal is a new salicylic acid derivative identified after a search for a compound with improved potency, enhanced gastrointestinal tolerance relative to its antiinflammatory activity, and a longer duration of action than that of aspirin. Animal and clinical studies have confirmed these properties. As an inhibitor of cyclooxygenase tested in vitro in a sheep seminal vesicle preparation, diflunisal was less potent than indomethacin but 10 to 20 times more active than aspirin. In addition, it was shown biochemically to act as a moderate free radical scavenger. Diflunisal is well absorbed from the gastrointestinal tract, is subject to dose-dependent pharmacokinetics (like aspirin), and reaches steady-state levels in a predictable fashion in most persons. The drug is excreted by the kidneys, and its apparent half-life is lengthened in the presence of renal failure. A number of drug interactions have been described. Diflunisal produces reversible effects on platelet aggregation when given in high doses, whereas aspirin produces irreversible aggregation at low doses. Measurements of fecal blood loss and endoscopic examinations have confirmed the improved gastrointestinal tolerance of diflunisal compared to aspirin., (1983 Pharmacotherapy Publications Inc.)

Diflunisal, 5-(2',4'-difluorophenyl) salicylic acid, was discovered as a potent antiinflammatory analgesic agent after an extensive investigation of more than 500 salicylic acid analogs. The addition of a difluorophenyl substituent at the C 5 position of salicylic acid yielded a new molecule with much improved lipophilicity, a longer duration of action, and a molecular configuration that is optimal for greater antiinflammatory and analgesic activities. The difluorophenyl group is metabolically stable; the acyl and phenolic glucuronides of the intact diflunisal are major urinary metabolites. The absence of an O-acetyl group in this novel salicylate analog circumvents the well-known in vivo acylation potential of aspirin and renders diflunisal a reversible cyclooxygenase inhibitor with a secondary oxygen radical scavenging effect. In a variety of analgesic, acute, and chronic antiinflammatory models, diflunisal is active at 10 mg/kg, approximately 5 to 10 times more potent than aspirin. It has a relatively low potential to cause gastrointestinal irritation as indicated by the lack of acute effect on the integrity of gastric mucosal barrier, no change of intragastric potential, and no disturbance of prostaglandin production by the gastric tissue. Diflunisal holds promise as a new clinically useful analgesic and antiinflammatory drug with good tolerance and a long duration of action., (1983 Pharmacotherapy Publications Inc.)

The effect of a high potency antacid and food on the bioavailability of famotidine was studied in 17 healthy volunteers in an open randomized three-way cross-over trial. After an overnight fast, famotidine was administered to each subject as follows: 40 mg famotidine orally alone; 40 mg orally with antacid; and 40 mg orally with a standard breakfast. Coadministration of the antacid caused a small but significant reduction in the maximum plasma concentration (Cmax) of famotidine from 81.1 +/- 54.2 to 60.8 +/- 21.6 ng ml-1 (P less than 0.05) and a small decrease in the area under plasma concentration-time curve [AUC] from 443.3 +/- 249.2 to 355.0 +/- 125.1 ng ml-1 h (P greater than 0.05). However, there was only a minimal effect of food on these parameters; the Cmax and [AUC] were 81.6 +/- 29.6 ng ml-1 and 434.8 +/- 145.9 ng ml-1 h, respectively.

The comparative effect of famotidine or cimetidine on theophylline disposition was determined in healthy volunteers. Cimetidine, but not famotidine, caused a reduction in the rate of elimination of theophylline. The mean total body clearance of theophylline was reduced from 57.6 ml min-1 before cimetidine to 39.5 ml min-1 during cimetidine; and the half-life was prolonged from 8.7 h before cimetidine to 12 h during cimetidine. The volume of distribution and renal excretion of theophylline were not affected by either famotidine or cimetidine.

1. The dose-peak effect relationship of lisinopril was evaluated in a double-blind, parallel study in 83 patients with mild to moderate essential hypertension (supine diastolic blood pressure = 95-115 mm Hg). 2. After a 4 week placebo washout, patients were randomly assigned to one of four treatments: lisinopril 2.5, 10, 20 or 80 mg day-1 for 1 week. 3. Lisinopril 10 and 20 mg day-1 produced similar peak antihypertensive effects which were greater than that produced by 2.5 mg day-1, but less than that of 80 mg day-1. If the incidence of first-dose symptomatic hypotension is related to the peak effect, then an initial lisinopril dose of 20 mg should not pose any greater risk than a 10 mg dose. 4. The magnitude of antihypertensive response at 24 h postdrug appeared to be dose related across the 2.5 to 80 mg day-1 range.

1. This was a multicentre, double-blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95-115 mm Hg) essential hypertension. 2. After a 4-week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5.20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks -2, 0, 2, 4, and 6. 3. There was a linear dose-response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day-1 groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day-1 groups. 4. Lisinopril, at doses up to 80 mg day-1, was well tolerated.

We have developed a method for measuring the efficacy of a single dose of an analgesic for 12 hours after administration to outpatients with postoperative oral surgery pain. Using a self-rating record, patients evaluate their pain and its relief for 12 hours after medication. We have used this method successfully in a series of three studies to compare diflunisal, a new nonsteroidal antiinflammatory analgesic, with placebo and aspirin 650 mg, acetaminophen 600 mg, propoxyphene napsylate 100 mg, or a combination of acetaminophen with either codeine 60 mg or propoxyphene 100 mg. Diflunisal evinced an unusually long duration of analgesic effect. In each study, all doses of diflunisal were significantly superior to placebo through the end of the 12-hour observation period, while the standards were superior for periods ranging from 2 to 7 hours. In terms of peak analgesia, diflunisal 1,000 mg was comparable to the acetaminophen-codeine combination and was significantly superior to all the other analgesic standards., (1983 Pharmacotherapy Publications Inc.)

1. The local responses to intradermal injection of PAF, histamine and PGE2 were investigated in eight healthy male volunteers. Acute effects were monitored by weal and flare measurement; delayed effects were investigated by pain threshold testing and skinfold thickness measurements. 2. PAF and PGE2 were found to induce weal and flare responses which were clearly distinguishable from vehicle and dose related. 3. PAF was approximately 50 times as potent as PGE2 at inducing weal on a molar basis. 4. A dose related hyperalgesia was recorded in response to PGE2. No hyperalgesia could be demonstrated following PAF injection compared with vehicle. 5. PAF and histamine elicited an increase in skinfold thickness up to 2 h after injection which was distinguishable from vehicle.