Simultaneous quantification of losartan and active metabolite in human plasma by liquid chromatography–tandem mass spectrometry using irbesartan as internal standard

A simple and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method employing electronspray ionization was developed and validated for quantification of losartan and its carboxylic acid metabolite in human plasma using irbesartan as internal standard (IS). Following a simple pretreatment procedure, the analytes were separated using a gradient mobile phase on reverse phase C₁₈ column. Selected reaction monitoring was specific for losartan, losartan acid and irbesartan. The method validation demonstrated the specificity, lower limit of quantification, accuracy and precision of measurements. The assay exhibited a linear dynamic range of 2.0–400 ng/mL for losartan and 1.85–370 ng/mL for losartan acid. A run time of 3.5 min for each sample made it possible to analyze more than 200 samples per day. The validated method has been successfully used to analyze human plasma samples for application in bioavailability/bioequivalence studies.     

Are constipation drugs effective and safe to be used in children? A review of the literature

INTRODUCTION: Functional constipation is a common and often enduring problem in childhood. Although functional constipation is well defined by the Rome III criteria, these criteria have not always been integrated in general practice. Early diagnosis and treatment are key factors with respect to successful long-term outcome, as chronic constipation has a negative effect on the quality of life and is a burden for the public healthcare system. The safety of laxatives used for paediatric-functional constipation is based on well-designed trials carried out mostly in adults. Therefore, we conducted a review of the literature outlining the evidence for the efficacy and safety of laxatives used in chronic paediatric-functional constipation. AREAS COVERED: This review clearly shows a lack of large well-designed placebo-controlled trials in children with constipation. Therefore, any interpretation with regards to the evidence for the effectiveness or safety of laxatives used in children is difficult and we extended the search for side effects to the adult literature. EXPERT OPINION: In adults, new promising drugs are on the virtue of breaking through in the treatment of chronic constipation. Carrying out well-defined placebo-controlled trials in children should be the next step before using these drugs.     

Can a proteomics strategy be used to identify the anti-malarial activity of chloroquine?

Interest in the mechanism of action of chloroquine is intense partly because of the emergence of drug-resistant parasites. Chloroquine resistance has been genetically linked to mutations in a parasite protein (PfCRT) that might confer resistance by inhibiting chloroquine accumulation in infected erythrocytes. Now chloroquine-binding proteins in malaria-infected erythrocytes, surprisingly, have been identified as human aldehyde dehydrogenase 1 and quinone reductase 2, raising the interesting possibility that the target of the anti-malarial activity of chloroquine might be a host enzyme.     

Which form of erythromycin should be used to treat gastroparesis? A pharmacokinetic analysis

Background:

Erythromycin is a macrolide antibiotic that exhibits prokinetic effects. It has been shown to enhance antral contractility and accelerates gastric emptying rates, primarily by stimulating motilin receptors.

Aim:

To determine the optimal dosage form of erythromycin for use as a prokinetic agent.

Methods:

Eight normal volunteers and three patients with documented gastroparesis ingested 250 mg erythromycin in tablet, suspension and intravenous forms. Serum erythromycin levels were determined at frequent intervals. These data were plotted vs. time and analysed for lag time, time to maximum concentration (t_max), maximum concentration (C_max) and bioavailability (F).

Results:

The absorption kinetics of the erythromycin suspension was notable for short lag times and early t_max, while lag times and t_max were delayed with the tablet form. Median lag time was 15 min for the suspension vs. 90 min for the tablet (P < 0.005). Median t_max for the suspension was 45 min vs. 180 min for the tablet (P < 0.005). A non-significant decrease in F was seen with the suspension compared to the tablet (P = 0.12).

Conclusion:

Based on the kinetic data from this study, erythromycin suspension is the ideal dosage form for administration of this drug as a prokinetic agent.

     

To be or not to be (inflamed)--is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?

A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.     

Small molecules as activators in medicinal chemistry (2000–2016)

Introduction: From therapeutic point of view, it is often beneficial to enhance the expression of certain enzymes whose low expression is responsible for the observed ailment. Small molecules as activators of several enzymes have great biological potential as anti-microbial and anti-cancer agents, for the treatment of diabetes, obesity, metabolic disorders, and for the treatment of neurological disorders including Alzheimer’s disease. This review covers patents describing small molecules as activators, and provides structural leads for the design of even more potent activators.

Area covered: This review is focused on small molecules that have been explored as activators of enzymes in the last and current decade (2000–2016).

Expert opinion: The ability to modulate activity of enzymes has long been a quest of medicinal chemistry. This has been the impetus behind the development of a plethora of drugs as enzyme inhibitors. However only a few enzyme activators as drugs have made it to the market. Disorders characterized by supressed enzyme activity can be treated by enhancing the activity of a specific enzyme.     

Responses of rat substantia nigra dopamine-containing neurones to (–)-HA-966 in vitro

1. Extracellular single unit recording techniques were used to compare the effects of (-)-3-amino-1-hydroxypyrrolidin-2-one ((–)-HA-966) and (±)-baclofen on the activity of dopamine-containing neurones in 300 μm slices of rat substantia nigra. Electrophysiological data were compared with the outcome of in vitro binding experiments designed to assess the affinity of (–)-HA-966 for γ-aminobutyric acid (GABA_B) receptors.
2. Bath application of (–)-HA-966 produced a concentration-dependent inhibition of dopaminergic neuronal firing (EC₅₀=444.0 μM; 95% confidence interval: 277.6 μM–710.1 μM, n=27) which was fully reversible upon washout from the recording chamber. Although similar effects were observed in response to (±)-baclofen, the direct-acting GABA_B receptor agonist proved to be considerably more potent than (–)-HA-966 (EC₅₀=0.54 μM; 95% confidence interval: 0.44 μM–0.66 μM, n=29) in vitro.
3. Low concentrations of chloral hydrate (10 μM) were without effect on the basal firing rate of nigral dopaminergic neurones but significantly increased the inhibitory effects produced by concomitant application of (–)-HA-966.
4. The inhibitory effects of (–)-HA-966 were completely reversed in the presence of the GABA_B receptor antagonists, CGP-35348 (100 μM) and 2-hydroxysaclofen (500 μM). Bath application of CGP-35348 alone increased basal firing rate. However, the magnitude of the excitation (9.2±0.3%) was not sufficient to account for the ability of the antagonist to reverse fully the inhibitory effects of (–)-HA-966.
5. (–)-HA-966 (0.1–1.0 mM) produced a concentration-dependent displacement of [^†H]-GABA from synaptic membranes in the presence of isoguvacine (40 μM). However, the affinity of the drug for GABA_B binding sites was significantly less than that of GABA (0.0005 potency ratio) and showed no apparent stereoselectivity.
6. These results indicate that while (–)-HA-966 appears to act as a direct GABA_B receptor agonist in vitro, its affinity for this receptor site is substantially less than that of GABA or baclofen and unlikely to account for the depressant actions of this drug which occur at levels approximately ten fold lower in vivo.

     

Enantioselective Determination of R-(-)-and S-( )-Mexiletine in Microsomal Incubates by Capillary gas Chromatography

本文建立了同时测定大鼠肝微粒体孵育液中Ｒ（）和Ｓ（＋）美西律的气相色谱／火焰离子化检测方法。首先，将美西律从微粒体孵育液中提取出来；然后，与手性试剂Ｓ（）Ｎ三氟乙酰基脯氨酰氯反应形成酰胺类非对映体衍生物；最后，采用高分辨毛细管气相色谱分离测定。分析方法的线性范围为５０～５０００μｇ／ｍｌ；平均回收率Ｒ（）美西律是９３３１±５５９％，Ｓ（＋）美西律是９３１０±５１１％（ｎ＝１０）；检测限是１０μｇ／ｍｌ，定量限是５０μｇ／ｍｌ（ＲＳＤ＜１６５％）。该法已用于Ｒ（）和Ｓ（＋）美西律在大鼠肝微粒体中的氧化代谢研究     

Can optical recordings of membrane potential be used to screen for drug-induced action potential prolongation in single cardiac myocytes?

INTRODUCTION: Potential-sensitive dyes have primarily been used to optically record action potentials (APs) in whole heart tissue. Using these dyes to record drug-induced changes in AP morphology of isolated cardiac myocytes could provide an opportunity to develop medium throughout assays for the pharmaceutical industry. Ideally, this requires that the dye has a consistent and rapid response to membrane potential, is insensitive to movement, and does not itself affect AP morphology. MATERIALS AND METHODS: We recorded the AP from isolated adult guinea-pig ventricular myocytes optically using di-8-ANEPPS in a single-excitation dual-emission ratiometric system, either separately in electrically field stimulated myocytes, or simultaneously with an electrical AP recorded with a patch electrode in the whole-cell bridge mode. The ratio of di-8-ANEPPS fluorescence signal was calibrated against membrane potential using a switch-clamp to voltage clamp the myocyte. RESULTS: Our data show that the ratio of the optical signals emitted at 560/620 nm is linearly related to voltage over the voltage range of an AP, producing a change in ratio of 7.5% per 100 mV, is unaffected by cell movement and is identical to the AP recorded simultaneously with a patch electrode. However, the APD90 recorded optically in myocytes loaded with di-8-ANEPPS was significantly longer than in unloaded myocytes recorded with a patch electrode (355.6+/-13.5 vs. 296.2+/-16.2 ms; p<0.01). Despite this effect, the apparent IC50 for cisapride, which prolongs the AP by blocking IKr, was not significantly different whether determined optically or with a patch electrode (91+/-46 vs. 81+/-20 nM). DISCUSSION: These data show that the optical AP recorded ratiometrically using di-8-ANEPPS from a single ventricular myocyte accurately follows the action potential morphology. This technique can be used to estimate the AP prolonging effects of a compound, although di-8-ANEPPS itself prolongs APD90. Optical dyes require less technical skills and are less invasive than conventional electrophysiological techniques and, when coupled to ventricular myocytes, decreases animal usage and facilitates higher throughput assays.     

Pharmacodynamic model for β-lactam regimens used in surgical prophylaxis: model-based evaluation of standard dosing regimens

Background Continual evolution of resistance among bacteria against methods of surgical prophylaxis may make currently used beta-lactam regimens inadequate. Objective To re-evaluate beta-lactam regimens in surgical prophylaxis. Setting A pharmacodynamic Monte Carlo simulation (MCS) model based on a number of patients in China. Methods Pharmacodynamic profiling using Monte Carlo simulation up to 4 hours postinfusion was conducted for standard-dose, short-term (0.5 h) and prolonged (2 to 4 h) infusions of ampicillin, cefazolin, cefotaxime, cefoxitin, cefuroxime, ertapenem, and piperacillin/tazobactam in adult patients with normal renal function. Microbiological data were incorporated. Cumulative fraction of response (CFR) was determined for each regimen against populations of S. aureus, coagulase-negative staphylococci and E. coli. The optimal CFR was defined as?≥?90% response. Main Outcome Measure Cumulative fractions of response of pharmacodynamic target attainment. Results During the first 2 hours postinfusion, piperacillin/tazobactam 3.375 g exhibited consistently optimal cumulative fractions against S. aureus, CoNS and E. coli. Ampicillin 2 g (2 h) also displayed optimal CFRs for S. aureus and E. coli but not for coagulase-negative staphylococci. Cefoxitin 2 g didnot achieve any optimal CFRs, even via 2-h prolonged infusion (maximum 72.8% CFR for S. aureus and 64.5% CFR for E. coli). Cefazolin 2 g (4 h) and cefuroxime 1.5 g (4 h) provided desired CFRs across 4 h postinfusion for S. aureus but provided poor CFRs for coagulase-negative staphylococci and E. coli. Only ertapenem 1 g for E. coli and S. aureus and cefotaxime 1 g for E. coli consistently yielded?≥?90% CFRs for 4 hour postinfusion. Conclusions Certain dosing regimens may warrant adjustment for improved prevention efficiency and enhanced empirical antibiotic regimens for surgical prophylaxis.     

Synthesis of silica chemisorbed bis(hydrogensulphato)benzene (SiO2–BHSB) as a new hybrid material and it's utility as an efficient,recyclable catalyst for the green synthesis of bis(indolyl)methanes

Synthesis of silica chemisorbed bis(hydrogensulphato)benzene (SiO₂-BHSB) was achieved as a new hybrid catalytic material, its structure, stoichiometry and stability was established using modern analytical techniques such as CP-MAS ¹³C NMR, CP-MAS ²⁹Si NMR, EDX, FT-IR, TGA and DTG. The synthesised material SiO₂–BHSB was observed as an environmentally benign, recyclable catalyst for the synthesis of bis(indolyl)methanes (BIMs) via an electrophilic substitution reaction of indoles by aldehydes or ketones under solvent free grinding condition. A range of structurally diverse aldehydes, ketones and indoles were smoothly undergone the developed catalytic protocol to offer good to excellent yields of corresponding bis(indolyl)methane derivatives in shorter reaction times. The synthesised material SiO₂–BHSB showed a sustained catalytic activity up to five cycles of its reuse for the synthesis of BIMs. The catalytic protocol offered a chemo-selective route for the synthesis of BIMs, in which aldehydes are pushed exclusively in presence of ketones to undergo the reaction. Simple working procedure, ease of isolation of the catalyst, environmentally compatible energy conditions and no side products are the additional salient features of this protocol.     

A systematic review of economic evaluation literature in Thailand: are the data good enough to be used by policy-makers?

In many countries, including Thailand, there is an increasing impetus to use economic evaluation to allow more explicit and transparent healthcare priority setting. However, an important question for policy makers in low- and middle-income countries is whether it is appropriate and feasible to introduce economic evaluation data into healthcare priority-setting decisions. In addition to ethical, social and political issues, information supply challenges need to be addressed. This paper systematically reviewed the literature on economic evaluation of health technology in Thailand published between 1982 and 2005. Its aim was to analyse the quantity, quality and targeting of economic evaluation studies that can provide a framework for those conducting similar reviews in other settings. The review revealed that, although the number of publications reporting economic evaluations has increased significantly in recent years, serious attention needs to be given to the quality of reporting and analysis. Furthermore, there is an absence of economic evaluation publications for 15 of the top 20 major health problems in Thailand, indicating a poor distribution of research resources towards the determination of cost-effective interventions for diminishing the disease burden of certain major health problems. If economic evaluation is only useful for policy makers when performed correctly and reported accurately, these findings depict information barriers to using economic evaluation to assist health decision-making processes in Thailand.     

Emulsification/internal gelation as a method for preparation of diclofenac sodium–sodium alginate microparticles

Emulsification/internal gelation has been suggested as an alternative to extrusion/external gelation in the encapsulation of several compounds including non-steroidal anti-inflammatory drugs such as diclofenac sodium. The objective of the present study was a trial to formulate diclofenac sodium as controlled release microparticles that might be administered once or twice daily. This could be achieved via emulsification/internal gelation technique applying Box-Behnken design to choose these formulae. Box-Behnken design determined fifteen formulae containing specified amounts of the independent variables, which included stirring speed in rpm (X1), drug:polymer ratio (X2) and the surfactant span 80% (X3). The dependent variables studied were cumulative percent release after two hours (Y1), four hours (Y2) and eight hours (Y3). The prepared microparticles were characterized for their production yield, sizes, shapes and morphology, entrapment efficiency and Diclofenac sodium in vitro release as well. The results showed that the production yield of the prepared diclofenac sodium microparticles was found to be between 79.55% and 97.41%. The formulated microparticles exhibited acceptable drug content values that lie in the range 66.20–96.36%. Also, the data obtained revealed that increasing the mixing speed (X1) generally resulted in decreased microparticle size. In addition, scanning electron microscope images of the microparticles illustrated that the formula contains lower span concentration (1%) in combination with lower stirring speed (200 rpm) which showed wrinkled, but smooth surfaces. However, by increasing surfactant concentration, microspheres’ surfaces become smoother and slightly porous. Kinetic treatment of the in vitro release from drug-loaded microparticles indicated that the zero order is the drug release mechanism for the most formulae.