PF-00547659 for the treatment of Crohn’s disease and ulcerative colitis

Introduction: Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells.

An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD).

Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD.

Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn’s disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD.     

Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis

Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials.

Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug.

Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.     

Simultaneous determination and pharmacokinetic analysis of seven alkaloids and two flavonoids from rat plasma by HPLC–DAD after oral administration of Wuzhuyu decoction

A simple and sensitive high-performance liquid chromatographic method was developed for the simultaneous determination and pharmacokinetic analysis of seven alkaloids dehydroevodiamine (DHED), 10-hydroxyrutaecarpine (HDR), evodiamine (EDM), rutaecarpine (RCP), 1-methyl-2-n-nonyl-4(1H)quinolone (MNQ), evocarpine (ECP), and dihydroevocarpine (DHE), and two flavonoids isorhamnetin-7-O-rutinoside (RIM) and diosmetin-7-O-β-d-glucopyranoside (GRD) in rat plasma after oral administration of Wuzhuyu decoction. The flow rate was kept at 1.0 ml/min and the detection wavelength was set at 300 nm. The calibration curves were linear in the range of 0.5013–30.076 μg/ml for DHED, 0.2161–21.608 μg/ml for RIM, 0.161–12.876 μg/ml for HDR, 0.2146–21.457 μg/ml for GRD, 2.0464–40.928 μg/ml for EDM, 1.0398–31.194 μg/ml for RCP, 0.5970–35.818 μg/ml for MNQ, 0.8371–20.928 μg/ml for ECP, and 0.5167–31.003 μg/ml for DHE. The precision (relative standard deviation (RSD), %) for all was less than 10% and the accuracy (relative error (RE), %) was within ± 10%. The results demonstrated that the assay had remarkable reproducibility with acceptable accuracy and precision. The lower limit of quantifications for the compounds in plasma ranged from 0.12 to 0.23 μg/ml and the lower limit of detections ranged from 0.024 to 0.076 μg/ml. This validated method has been successfully applied in the pharmacokinetics study of seven alkaloids and two flavonoids after orally administrating the Wuzhuyu decoction to rats.     

Binding affinity of levomepromazine and two of its major metabolites to central dopamine and α-adrenergic receptors in the rat

N-Monodesmethyl levomepromazine and levmepromazine sulfoxide have previously been found in higher plasma concentrations than the parent drug in patients who received oral doses of levomepromazine. In the present study levomepromazine, N-monodesmethyl levomepromazine and levomepromazine sulfoxide have been assayed for their binding affinity to rat striatal dopamine receptors and to -adrenergic receptors in rat cortex, and compared with the potency of chlorpromazine and some of its metabolites in the same systems. Levomepromazine sulfoxide was relatively inactive in the dopamine receptor binding test but much more active in the -adrenergic receptor binding test, where it had a binding affinity similar to 7-hydroxy chlorpromazine. Levomepromazine and N-monodesmethyl levomepromazine were active in both systems, having a slightly higher potency than chlorpromazine in the -adrenergic binding test, and a somewhat lower potency than chlorpromazine in the dopamine receptor binding test. The results indicate that N-monodesmethyl levomepromazine may significantly contribute to the antipsychotic effects of levomepromazine while the sulfoxide metabolite lacks neuroleptic potency, and that both metabolites may contribute to the autonomic side-effects of the drug.     

Free and/or glucuronidated Danshensu, protocatechuic aldehyde, protocatechuic acid and caffeic acid are potentially pharmacological components in rats after oral administration of extractum for Compound DanShen Dripping Pill

AIM： To provide primarily pharmacokinetic profiles and reveal potentially pharmacological components after oral administration of the extractum for Compund Danshen Dripping Pill （CDDP） in rats, which was mainly composed of protocatechuic aldehyde （PAL）, Danshensu （DSS）, lithospermic acid A, lithospermic acid B, salvianolic acid D, rosmarinic acid, salvianolic acid B and salvianolic acid A. METHODS： After orally administration of 200 mg CDDP extractum for 1 h, the portal vein blood, the femoral artery blood, the bile and urine samples were separately collected. The gastrointestinal （GI） contents and mucosa were washed with physiological saline and the washing solution was pooled. The whole GI tract was removed and homogenized for analysis. The constituents and concentrations of all above samples were determined by the LC-MS analysis combined with the β-glucuronidase and sulfatase treatment. RESULTS： The investigation after oral administration of CDDP extractum for 1 h in rats indicated that： （1）Most of polyphenolic acids have been degraded into caffeic acid （CA） and DSS in the GI tract. Next, CA could be easily absorbed into blood circulation and a trace of DSS was also transported into the portal vein. The remains of undegraded polyphenolic acids and Danshensu were detained in the GI tract lumen. （2）Part of PAL was firstly oxidized into PAC in GI epithelial cells before absorption into the portal vein. Next, PAC and the rest PAL were further transported into blood circulation. （3）PAC and PAL were distributed in blood circulation in free and conjugated forms after being glucuronidated in the liver and the kidney while only free CA and DSS appeared in vivo. After that, all of these metabolites were gradually secreted into bile and urine.[第一段]     

A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects

Objective To investigate the pharmacokinetics of S-omeprazole (esomeprazole), R-omeprazole and racemic omeprazole following single and repeated oral doses of 20 mg and 40 mg of each compound in healthy male and female subjects.Methods In an open, randomised, three-way, cross-over study, 12 subjects received 20 mg and another 12 subjects received 40 mg S-omeprazole, R-omeprazole and racemic omeprazole as oral solutions once daily for 5 days, separated by washout periods of at least 10 days. Blood samples were taken for analysis pre-dose and at selected time points during a 12-h period following drug administration on study day 1 and day 5. Pharmacokinetic parameters of S-omeprazole, R-omeprazole, racemic omeprazole and the two main metabolites (5-hydroxy and sulphone) were calculated using non-compartmental analysis.Results Following the 20-mg dose of each compound, values of the total area under the plasma concentration–time curve (AUC) were 1.52, 0.62 and 1.04 mol h/l for S-omeprazole, R-omeprazole and racemic omeprazole, respectively, on day 1. Respectively, AUC values on day 5 were 2.84, 0.68 and 1.63 mol h/l. Corresponding values after the 40-mg doses were 3.88, 1.39 and 2.44 mol h/l on day 1 and 9.32, 1.80 and 5.79 mol h/l on day 5.Conclusion Treatment with S-omeprazole (esomeprazole; 20 mg and 40 mg) resulted in higher AUC values than with either R-omeprazole or racemic omeprazole after both single and repeated doses due to a lower metabolic rate of S-omeprazole than R-omeprazole and, consequently, racemic omeprazole. S-Omeprazole, R-omeprazole and the racemate were well tolerated.     

Simultaneous determination of tolterodine and its two metabolites, 5-hydroxymethyltolterodine and <Emphasis Type="Italic">N</Emphasis>-dealkyltolterodine in human plasma using LC–MS/MS and its application to a pharmacokinetic study

Tolterodine is a nonselective muscarinic antagonist that is indicated for the overactive urinary bladder and other urinary difficulties. We developed and validated a simple, rapid and sensitive high-performance liquid chromatography analytical method utilizing tandem mass spectrometry (LC–MS/MS) for the quantitation of tolterodine and its major metabolites, 5-hydroxymethyltolterodine (5-HMT) and N-dealkyltolterodine (NDT), in human plasma. After liquid–liquid extraction with methyl t-butyl ether, chromatographic separation of the three analytes was achieved using a reversed-phase Luna Phenyl-hexyl column (100 × 2.0 mm, 3 μm particles) with a mobile phase of 10 mM ammonium formate buffer (pH 3.5)-methanol (10:90, v/v) and quantified by MS/MS detection in electrospray ionization (ESI) positive ion mode. The retention time of tolterodine, 5-HMT, NDT, and internal standard (IS) were 1.4, 1.24, 1.33, and 1.26 min, respectively. The calibration curves were linear over a range of 0.025–10 ng/ml for tolterodine and 5-HMT, and 0.05–10 ng/ml for NDT. The lower limit of quantifications using 200 μl of human plasma was 0.025 ng/ml for tolterodine and 5-HMT, and 0.05 ng/ml for NDT. The mean accuracy and precision for intra- and inter-run validation of tolterodine, 5-HMT, and NDT were all within acceptable limits. These results showed that a simple, rapid and sensitive LC–MS/MS method for the quantification of tolterodine and its major metabolites in human plasma was developed. This method was successfully applied to a pharmacokinetic study in humans.     

Simultaneous determination of baicalin,baicalein, wogonin,berberine, palmatine and jatrorrhizine in rat plasma by liquid chromatography–tandem mass spectrometry and application in pharmacokinetic studies after oral administration of traditional Chinese medicinal preparations containing scutellaria–coptis herb couple

A sensitive, rapid and selective liquid chromatography–tandem mass spectrometry (LC–MS–MS) method was developed and validated for the simultaneous determination of baicalin, baicalein, wogonin, berberine, palmatine and jatrorrhizine in scutellaria–coptis herb couple in rat plasma. After protein precipitation with acetonitrile and 0.1% NaH₂PO₄, chromatography was performed using a C₁₈ column, with gradient elution with 0.1% formic acid and acetonitrile at 0.25 ml/min. All analytes including internal standards were monitored under positive ionization conditions by selected reaction monitoring with an electrospray ionization source. The lower limit of quantification was 10 ng/ml for baicalin, baicalein and wogonin, and 0.6 ng/ml for berberine, palmatine and jatrorrhizine. The validated method was applied in pharmacokinetic studies after oral administration of Yiqing Capsule and Gegen-Qinlian Tablet to rats.     

An open comparative study of two diuretic combinations,frusemide/amiloride (‘Frumil’) and bumetanide/potassium chloride (‘Burinex’ K), in the treatment of congestive cardiac failure in hospital out-patients

Summary

Forty elderly patients, aged 68 to 89 years, with congestive cardiac failure, who were attending a hospital out-patients department, entered an open, parallel group, comparative study of two diuretic combinations, 40 mgfrusemide plus 5?mg amiloride per tablet and 0.5?mg bumetanide plus 573?mg slow-release potassium chloride per tablet. Patients were assigned at random to receive one or other combination for 8 weeks, dosage being determined by the severity of the individual patient's condition (range 1 to 3 tablets frusemide/amiloride; 2 to 6 tablets bumetanide/potassium chloride). Clinical assessments, including visual analogue scores for dyspnoea at rest and on effort, and laboratory measurements of serum potassium and magnesium levels were carried out on entry and after 2, 4 and 8 weeks of treatment. Other variables were monitored before, during and/or after treatment. Although significant decreases were reported in dyspnoea severity scores at rest and on effort only in the bumetanide/potassium chloride group, global assessment of the patients' condition by patient and clinician at the end of the study indicated that both treatments produced improvement, and a greater proportion of patients considered treatment as satisfactory in the frusemide/amiloride group. Both drug combinations were well-tolerated and only a few minor side-effects were reported. Serum potassium levels were maintained in both treatment groups but there was a significant decrease in mean serum magnesium levels in patients on bumetanide/potassium chloride. Hyponatraemia was also detected in 2 patients on this combination. An increase in body weight was recorded in both groups, the increase being significant in patients receiving bumetanide/potassium chloride.     

Estimating the comparative efficacy of cladribine tablets versus alternative disease modifying treatments in active relapsing–remitting multiple sclerosis: adjusting for patient characteristics using meta-regression and matching-adjusted indirect treatment comparison approaches

Objectives: To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) – fingolimod, natalizumab, alemtuzumab and ocrelizumab – in adults with active relapsing–remitting multiple sclerosis (RRMS), using meta-regression to provide subpopulation-specific estimates of drug effect. Additionally, to determine the feasibility of conducting a matching-adjusted indirect comparison (MAIC) to validate the meta-regression results.

Methods: A published systematic literature review (SLR) identified studies evaluating the efficacy of cladribine tablets and alternative DMTs in the management of active RRMS. A series of meta-regression models were run with adjustment for baseline risk, fitted to data from the intention-to-treat cohorts of trials identified in the SLR. A non-parametric MAIC analysis adjusted for differences between studies by reweighting patient-level data from the index trial to match the mean baseline characteristics reported for trials with only aggregate data.

Results: The meta-regression analysis showed significant overlap in credible intervals for the hazard ratios of 6 month confirmed disability progression (CDP-6M) and annualized relapse rate (ARR), with no therapy statistically dominating in terms of efficacy and all therapies estimated to reduce the ARR compared to placebo in all subpopulations. In the MAIC analysis, cladribine tablets showed a reduction in CDP-6M and ARR comparable to alemtuzumab before and after matching.

Conclusion: This analysis has demonstrated that cladribine tablets have comparable relative efficacy to other highly efficacious DMTs in active RRMS across all subpopulations, thus validating the comparative effectiveness results from previous network meta-analysis. The MAIC analysis showed that cladribine tablets are comparable in efficacy to alemtuzumab in the treatment of patients with RRMS.