Stereospecific Pharmacokinetics and Pharmacodynamics of Beta-Adrenergic Blockers in Humans

The beta-blockers comprise a group of drugs that are mostly used to treat cardiovascular disorders such as hypertension, cardiac arrhythmia, or ischemic heart disease. Each of these drugs possesses at least one chiral center, and an inherent high degree of enantioselectivity in binding to the b-adrenergic receptor. For beta-blockers with a single chiral center, the (-) enantiomer possesses much greater affinity for binding to the b-adrenergic receptors than antipode. The enantiomers of some of these drugs possess other effects, such as antagonism at alpha-adrenergic receptors or Class III antiarrhythmic activity. However, these effects generally display a lower level of stereoselectivity than the beta-blocking activity. Except for timolol, all of these drugs used systemically are administered clinically as the racemate. As a class, the beta blockers are quite diverse from a pharmacokinetic perspective, as they display a high range of values in plasma protein binding, percent of drug eliminated by metabolism or unchanged in the urine, and in hepatic extraction ratio. With respect to plasma concentrations attained after oral or intravenous dosing, in most cases the enantiomers of the beta-blockers show only a modest degree of stereoselectivity. However, the relative magnitude of the concentrations of the enantiomers in plasma is not constant in all situations and varies from drug to drug. Further, various factors related to the drug (e.g., dosing rate or enantiomer-enantiomer interaction) or the patient (e.g., racial background, cardiovascular function, or the patient metabolic phenotype) may affect the stereospecific pharmacokinetics and pharmacodynamics of beta-blockers. An understanding of the stereospecific pharmacokinetics and pharmacodynamics of beta-blockers may help clinicians to interpret and predict differences among patients in pharmacologic responses to these drugs

Climate change-driven losses in ecosystem services of coastal wetlands: A case study in the West coast of Bangladesh

© 2018 The Authors Climate change is globally recognized as one of the key drivers of degradation of coastal wetland ecosystems, causing considerable alteration of services provided by these habitats. Quantifying the physical impacts of climate change on these services is therefore of utmost importance. Yet, practical work in this field is fragmented and scarce in current literature, especially in developing countries which are likely to suffer most from the adverse climate change impacts. Using a coherent scenario-based approach that combines assessment of physical impacts with economic valuation techniques, here we quantify potential climate change driven losses in the value of wetland ecosystems services due to relative sea-level rise (RSLR)-induced inundation in the vulnerable Western coastal area of Bangladesh in 2100. The results show a small inundation area in 2100 under the three IPCC climate scenarios of RCP2.6 (with 0.25 m of RSLR), RCP6.0 (with 1.18 m of RSLR), and RCP8.5 (with 1.77 m of RSLR) for the coastal wetland ecosystems including the Sundarbans mangrove forest, neritic system and aquaculture ponds. In all scenarios, RSLR will drive a loss in the total value of ecosystem services such as provision of raw materials, and food provision, ranging from US$0–1 million to US$ 16.5–20 million, respectively. The outcomes of this study reveal that RSLR-induced inundation on its own, is unlikely to be a major threat to the wetland ecosystems in Western coast of Bangladesh. This would suggest that other climate change impacts such as coastal erosion, increase in frequency of cyclone events, and sea temperature rise might be the likely primary drivers of change in the value of wetland ecosystems services in this area

Liquid Chromatography-Tandem Mass Spectrometry for the Determination of Methylprednisolone in Rat Plasma and Liver After Intravenous Administration of Its Liver-Targeted Dextran Prodrug

A specific and sensitive liquid chromatography (LC)-tandem mass spectrometric method for quantitative determination of methylprednisolone (MP) in rat plasma and liver was developed and validated using triamcinolone acetonide as an internal standard. Liquid-liquid extraction using tert-butyl methyl ether was used to extract the drug and the internal standard from plasma and liver. The separation of MP was performed on a C(18) column with a mobile phase of acetonitrile:0.5% formic acid aqueous solution (85:15, v/v) over 4 min. The assay was based on the selected reaction monitoring transitions at m/z 375 -\u3e 161 for MP in plasma, 375 -\u3e 357 for MP in liver, and 435 -\u3e 415 for internal standard in both plasma and liver. The lower limit of quantification was 20 ng/mL based on 100 mu L of plasma or liver homogenate. Intra- and inter-clay assay variations wer

Computational Opioid Prescribing: A Novel Application of Clinical Pharmacokinetics

We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist pre-scribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety

Dextran and its potential use as tablet excipient

Dextrans are a class of carbohydrate polymers extensively applied in pharmaceutical applications, particularly as drug conjugate macromolecular carriers or drug delivery systems. These polysaccharides improve the stability of the therapeutics enabling also the control of their release, via either the parenteral and or oral routes. In the latter case, due to their gel forming ability they may have potential as hydrophilic matrix tablets for sustained drug release. In this paper, we investigated the behaviour of different molecular weight (1, 40, 500 and 2300 kDa) dextrans as tabletting excipients. Powder particle size and hygroscopic studies have been reported, together with tabletability, tablet stability and tablet swelling. Moreover we use tramadol as model compound to evaluate the ability of dextrans to control drug dissolution. The results suggest that dextrans with lower molecular weights may be a promising excipient to be used as filler for immediate release tablets, due to their good tabletability and fast dissolution rate, while dextrans with higher molecular weights could be an efficient disintegrant due to their swelling ability

Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

<p>Abstract</p> <p>Background</p> <p>Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (<it>Neurology </it>2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD.</p> <p>Methods</p> <p>Subjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale.</p> <p>Results</p> <p>Of the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg).</p> <p>Conclusions</p> <p>TBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia.</p> <p>Trial Registration</p> <p>Clinicaltrials.gov registration number (initial study): NCT00219804</p

Stereoselective, competitive, and nonlinear plasma protein binding of ibuprofen enantiomers as determined in vivo in healthy subjects

The plasma protein binding and competitive inhibition parameters of R(−)- and S(+)-ibuprofen were determined in vivo in 12 healthy subjects. Subjects participated in a 4×4 Latin square design in which oral solutions of drug were administered as 300 mg R (−)-ibuprofen, 300 mg S (+)-ibuprofen, 300 mg R (−)-+300 mg S (+)-ibuprofen, and 300 mg R(−)-+600 mg S (+)-ibuprofen. Unlabeled ibuprofen enantiomers were quantitated using a stereospecific reversed-phase HPLC assay, and plasma protein binding experiments were performed using radiolabeled 14 C-enantiomers and an ultrafiltration method at 37C. At therapeutic drug concentrations, the protein binding of each enantiomer was greater than 99%. Furthermore, the binding of ibuprofen enantiomers was Stereoselective and mutually competitive, as well as nonlinear. The bound-free data were fitted to a model in which the non-linearity of plasma protein binding and competition between enantiomers for binding sites could be accommodated. There were substantial differences in the affinity of ibuprofen enantiomers for protein binding sites (RP2=0.358±0.185 vs. SP2=0.979 ±0.501 μg/ml; X±SD) but no differences in their binding capacity (RP1=160±86 vs. SP1=161 ±63 μg/ml). Although statistically significant, the differences in competitive inhibition parameters were more modest (SKI=0.661 ±0.363 vs. RKI=0.436 ±0.210 μg/ml). As a result, the intrinsic binding (i.e.), P1/P2J of R(−)-ibuprofen was greater than S(±)-ibuprofen, and the unbound fraction was significantly greater for S-enantiomer vs. R-enantiomer after a given dose of R-ibuprofen or racemate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45048/1/10928_2005_Article_BF01059767.pd