Dual Elimination Research Articles

Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.

Palladium-Catalyzed Arylation of a Sterically Demandinggem-Dibromophosphaethene

The trans bromide of 2,2-dibromo-1-(2,4,6-tri-t-butylphenyl)-1-phosphaethene (Mes*P=CBr2; Mes*=2,4,6-tBu3C6H2) can be successfully substituted with an aryl group by using a palladium version of the Kumada-Tamao-Corriu cross-coupling process. Predominant formation of the 2-aryl-2-bromo-1-phosphaethene [(Z)-Mes*P=C(Br)Ar] required suitable conditions including optimization of the ancillary phosphine ligand, thereby retarding the dual elimination of bromides leading to phosphaalkyne (Mes*C≡P). The 2-aryl-2-bromo-1-phosphaethenes hold promise as versatile synthons for functional π-conjugated molecules, and stereospecific transformations of the bromine atom by halogen-metal exchange and palladium-catalyzed arylations were demonstrated.

Grid-friendly Control Strategy with Dual Primary-Side Series-Connected Winding Transformers

High-power three-level voltage-source converters are widely utilized in high-performance AC drive systems. In several ultra-power instances, the harmonics on the grid side should be reduced through multiple rectifications. A combined harmonic elimination method that includes a dual primary-side series-connected winding transformer and selective harmonic elimination pulse-width modulation is proposed to eliminate low-order current harmonics on the primary and secondary sides of transformers. Through an analysis of the harmonic influence caused by dead time and DC magnetic bias, a synthetic compensation control strategy is presented to minimize the grid-side harmonics in the dual primary side series-connected winding transformer application. Both simulation and experimental results demonstrate that the proposed control strategy can significantly reduce the converter input current harmonics and eliminates the DC magnetic bias in the transformer.

In situ dual-functional water purification with simultaneous oil removal and visible light catalysis.

Dual purification of both oily wastewater and dye-polluted water for enhancing the use of freshwater is an urgent task. We report herein, the facile synthesis of inorganic semiconductor nanomaterials anchored mesh for in situ dual-functional water purification. This resultant mesh combines the excellent capacity of oil removal and the advantage of photocatalytic performance for dye degradation under visible light irradiation at the same time. In addition, the mesh was easily regenerated and remained unaltered in photocatalytic performance over five successive dye degradation cycles. Given the innovative integration of special wettability and photocatalytic activity of such a semiconductor material under visible light for dual elimination of various pollutants from water, we anticipate that this approach will provide a promising pathway for versatile applications in oily wastewater treatment, water purification and so on.

Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults.

Background and ObjectivesDasotraline is a novel inhibitor of dopamine and norepinephrine reuptake currently being investigated in clinical studies for the treatment of attention-deficit/hyperactivity disorder (ADHD). Uniquely, relative to current ADHD medications, dasotraline has a slow absorption and long elimination half-life. Here we relate the pharmacokinetics and pharmacodynamics of dasotraline to reduction in ADHD symptoms based on simulated clinical trial outcomes.MethodsDasotraline pharmacokinetics were analyzed by population pharmacokinetic methodologies using data collected from 395 subjects after single or multiple oral dose administrations ranging from 0.2 to 36 mg (three phase I studies and one phase II ADHD study). Population pharmacokinetic and pharmacodynamic models related individual dasotraline exposures to norepinephrine metabolite 3,4-dihydroxyphenylglycol (DHPG) concentrations, ADHD symptoms, and study discontinuation (probability of dropout).ResultsDasotraline pharmacokinetics were described by a one-compartment model with dual (linear plus nonlinear) elimination. In an ADHD population treated with dasotraline 4 or 8 mg/day, dasotraline was characterized by a mean apparent half-life of 47 h and plasma concentrations reached steady-state by 10 days of dosing. A population pharmacokinetic and pharmacodynamic model of DHPG indicated clinically significant norepinephrine transporter inhibition was achieved as a function of time-matched dasotraline concentrations. Dasotraline exposure reduced ADHD symptoms in a sigmoid Emax time-course model. Clinical trial simulations described the effects of dose, duration, and sample size on clinical outcomes.ConclusionThese results related dasotraline pharmacokinetics to pharmacological activity in ADHD, and support the novel concept that maintaining constant, steady-state dopamine and norepinephrine reuptake inhibition throughout a 24-h dosing interval is a novel pharmacological approach to the management of ADHD symptoms.Clinicaltrials.gov identifier: NCT01692782.Electronic supplementary materialThe online version of this article (doi:10.1007/s40261-015-0358-7) contains supplementary material, which is available to authorized users.

S16.1 Eliminating mother to child transmission of hiv and syphilis

The Initiative for Global Elimination of Congenital Syphilis was launched in 2007, and the Global Plan towards the Elimination of New HIV Infections among Children by 2015 and Keeping Their Mothers Alive was launched in 2010. In 2014, the World Health Organization, jointly with UNAIDS, UNICEF, UNFPA, and other global partners released guidance on the processes and criteria for dual elimination of mother-to-child transmission (MTCT) of HIV and syphilis. Countries all over the world are now striving for dual elimination. This presentation will address recent successes like Cuba and current strategies and new tools that can help to overcome barriers in the dual elimination of MTCT HIV and syphilis with a particular focus on MTCT of syphilis.

Connecting the Dots: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model

The goal of this work was to extend a mathematical, multiscale systems model of bone function, remodeling, and health in order to explore hypotheses related to therapeutic modulation of sclerostin and quantitatively describe purported osteocyte activity within bone remodeling events. A pharmacokinetic model with first-order absorption and dual elimination pathways was used to describe the kinetics of romosozumab, a monoclonal antibody (mAb) against sclerostin. To describe total circulating sclerostin, an extended indirect response model of inhibition of offset was developed. These models were subsequently linked to the systems model, with sclerostin signaling changes in resorption and formation through established osteocyte-mediated mechanisms. The model proposes relative contributions of the osteocyte to the RANKL pool, a major player in feedback signaling, and is used to explore hypotheses surrounding attenuation of anabolic activity after multiple doses of sclerostin mAbs, a phenomenon whose mechanism is poorly understood.

Prevention of mother-to-child transmission of syphilis and HIV in China: What drives political prioritization and what can this tell us about promoting dual elimination?

ObjectiveThe present study aims to identify reasons behind the lower political priority of mother-to-child transmission (MTCT) of syphilis compared with HIV, despite the former presenting a much larger and growing burden than the latter, in China, over the 20years prior to 2010. MethodsWe undertook a comparative policy analysis, based on informant interviews and documentation review of control of MTCT of syphilis and HIV, as well as nonparticipant observation of relevant meetings/trainings to investigate agenda-setting prior to 2010. ResultsWe identified several factors contributing to the lower priority accorded to MTCT of syphilis: relative neglect at a global level, dearth of international financial and technical support, poorly unified national policy community with weak accountability mechanisms, insufficient understanding of the epidemic and policy options, and a prevailing negative framing of syphilis that resulted in significant stigmatization. ConclusionA dual elimination goal will only be reached when prioritization of MTCT of syphilis is enhanced in both the international and national agendas.

Elimination of mother-to-child transmission of HIV and syphilis: A dual approach in the African Region to improve quality of antenatal care and integrated disease control

The World Health Organization’s (WHO) Strategic Framework for the Elimination of New HIV Infections among Children in Africa by 2015 identifies important synergies for the elimination of mother-to-child transmission of HIV and syphilis in terms of prevention interventions, implementation logistics and service delivery, monitoring and evaluation systems, and need for sustained political commitment. The WHO advocates the use of an integrated, rights-based dual approach with partnerships and collaboration to make the best use of available resources. Through a consultative approach, six countries in the African Region committed to dual elimination and developed and implemented action plans for this purpose. Where interest and commitment are high, this may also be possible and effective in other African countries.

O321: Progress of the dual elimination of mother to child transmission of HIV and congenital syphilis in Latin America and the Caribbean

O321: Progress of the dual elimination of mother to child transmission of HIV and congenital syphilis in Latin America and the Caribbean

Modeling and Simulation Support Eltrombopag Dosing in Thrombocytopenic Patients with Chronic HCV Infection

The pharmacokinetics of eltrombopag and its stimulation of platelet production were characterized in patients with chronic hepatitis C virus (HCV) infection to optimize an eltrombopag dosing regimen for treatment of HCV-related thrombocytopenia before and throughout peginterferon (pegIFN)-based antiviral therapy. Population pharmacokinetic analysis for eltrombopag included 663 individuals (healthy subjects, n = 28; patients with HCV, n = 635). Population pharmacokinetic/pharmacodynamic analysis for platelet response involved patients with HCV only. Simulations were conducted using various dosing scenarios in the same patient population. Eltrombopag pharmacokinetics were described by a two-compartment model with dual sequential first-order absorption and elimination. Age, race, sex, and severity of hepatic impairment were predictors of eltrombopag clearance. The effect of eltrombopag on platelet counts was adequately described by a model with four transit compartments in which eltrombopag concentrations stimulated the production rate of platelet precursors in an Emax manner. Modeling and simulation results support once-daily eltrombopag 25mg as an appropriate starting dosing regimen followed by biweekly dose escalation (in 25-mg increments) up to once-daily eltrombopag 100mg to raise platelet counts sufficiently for initiation of pegIFN-based antiviral therapy in patients with HCV. Biweekly dose adjustment allows patients to stay on the lowest possible eltrombopag dose during antiviral therapy.

Dalbavancin: Roles for Once-Weekly Antibiotics in Difficult to Treat Gram-Positive Infections

Skin and soft-tissue infections (SSTI) are on the rise, accounting for nearly 3.5 million ED visits in 2010. In a world with a rising prevalence of multi-drug resistance organisms it has become imperative to create novel antibiotics for the 21st century. A new once-weekly antibiotic, Dalbavancin (Durata Therapeutics, INC), has shown great promise and was recently approved by the FDA for patients with SSTI cause by gram-positive microorganisms, including MRSA. Dalbavancin has been shown to have equal efficacy for SSTI caused by gram-positive infections when compared to vancomycin and linezolid. In addition, it has a favorable pharmacokinetic profile that allows for once-weekly IV infusion, leading to the possibility of outpatient therapy even for severe SSTI. It undergoes dual elimination via urine and feces and dose adjustment for patients with renal and hepatic impairment does not appear necessary. It is well tolerated without evidence of hepatic or renal toxicity, gastrointestinal flora alteration, or significant drug–drug interaction. This review aims to summarize the clinical research already preformed on dalbavancin and describes its role in the clinical antibiotic armamentarium.

Reaction of diphenyl ditelluride with 2,3-dichloroprop-1-ene in the system hydrazine hydrate-KOH

Diphenyl ditelluride reacts with 2,3-dichloroprop-1-ene in the system hydrazine hydrate-KOH along several parallel routes. Beside the nucleophilic chlorine substitution at the sp 3-hybridized carbon atom resulting in 2-chloro-3-phenyltellanylprop-1-ene the elimination of both chlorine atoms occurs affording a mixture of allene and methylacetylene. The reasons of the dual elimination reaction paths are considered.

A Biodistribution and Toxicity Study of Cobalt Dichloride-N-Acetyl Cysteine in an Implantable MRI Marker for Prostate Cancer Treatment

C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate. 9-μL doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated. No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 μg/g and 268 μg/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 ± 5.6% (liver), >11.8 ± 6.5% (prostate), and >5.3 ± 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 μg/mL at 5-60 minutes). Excretion in urine was 13.1 ± 4.6%, with 3.1 ± 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed. C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy.

The Glucagon-Like Peptide-1 Receptor Agonist Exendin 4 Has a Protective Role in Ischemic Injury of Lean and Steatotic Liver by Inhibiting Cell Death and Stimulating Lipolysis

Nonalcoholic fatty liver disease is an increasingly prevalent spectrum of conditions characterized by excess fat deposition within hepatocytes. Affected hepatocytes are known to be highly susceptible to ischemic insults, responding to injury with increased cell death, and commensurate liver dysfunction. Numerous clinical circumstances lead to hepatic ischemia. Mechanistically, specific means of reducing hepatic vulnerability to ischemia are of increasing clinical importance. In this study, we demonstrate that the glucagon-like peptide-1 receptor agonist Exendin 4 (Ex4) protects hepatocytes from ischemia reperfusion injury by mitigating necrosis and apoptosis. Importantly, this effect is more pronounced in steatotic livers, with significantly reducing cell death and facilitating the initiation of lipolysis. Ex4 treatment leads to increased lipid droplet fission, and phosphorylation of perilipin and hormone sensitive lipase - all hallmarks of lipolysis. Importantly, the protective effects of Ex4 are seen after a short course of perioperative treatment, potentially making this clinically relevant. Thus, we conclude that Ex4 has a role in protecting lean and fatty livers from ischemic injury. The rapidity of the effect and the clinical availability of Ex4 make this an attractive new therapeutic approach for treating fatty livers at the time of an ischemic insult.

Pharmacokinetics of salsalate and salicylic acid in normal and diabetic rats

The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto-Kakizaki rats. Three PK studies were conducted: (1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. (2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. (3) PK during 4 months feeding of SS-containing diet in both normal and diabetic rats. The disposition of SS and SA were evaluated simultaneously using a pharmacokinetic model comprising several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing of SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS-diet feeding, the diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F), possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in the future usage of SS in diabetes.

Niveau de preuve du suivi thérapeutique pharmacologique de la ceftriaxone

Ceftriaxone is a third generation cephalosporin with an original pharmacokinetics based on a long elimination half-life among cephalosporins, a high protein binding and a dual renal and biliary elimination. Also the pharmacokinetic parameters of ceftriaxone are highly variable in clinical situations such as severe renal insufficiency, liver and renal insufficiency, the elderly, the neonates less than 1 week of age and critically ill patients. In these clinical situations associated or not with high minimal inhibitory concentration (MIC) level, the relationship concentration-clinical outcome based on the ratio between trough plasma concentration and MIC can allow a dose adjustment. Consequently, therapeutic drug monitoring (TDM) of ceftriaxone could be possibly useful in these situations, whereas the necessity of TDM has still to be demonstrated to monitor toxicity.

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis

Disordered glucagon secretion contributes to the symptoms of diabetes, and reduced glucagon action is known to improve glucose homeostasis. In mice, genetic deletion of the glucagon receptor (Gcgr) results in increased levels of the insulinotropic hormone glucagon-like peptide 1 (GLP-1), which may contribute to the alterations in glucose homeostasis observed in Gcgr-/- mice. Here, we assessed the contribution of GLP-1 receptor (GLP-1R) signaling to the phenotype of Gcgr-/- mice by generating Gcgr-/-Glp1r-/- mice. Although insulin sensitivity was similar in all genotypes, fasting glucose was increased in Gcgr-/-Glp1r-/- mice. Elimination of the Glp1r normalized gastric emptying and impaired intraperitoneal glucose tolerance in Gcgr-/- mice. Unexpectedly, deletion of Glp1r in Gcgr-/- mice did not alter the improved oral glucose tolerance and increased insulin secretion characteristic of that genotype. Although Gcgr-/-Glp1r-/- islets exhibited increased sensitivity to the incretin glucose-dependent insulinotropic polypeptide (GIP), mice lacking both Glp1r and the GIP receptor (Gipr) maintained preservation of the enteroinsular axis following reduction of Gcgr signaling. Moreover, Gcgr-/-Glp1r-/- islets expressed increased levels of the cholecystokinin A receptor (Cckar) and G protein-coupled receptor 119 (Gpr119) mRNA transcripts, and Gcgr-/-Glp1r-/- mice exhibited increased sensitivity to exogenous CCK and the GPR119 agonist AR231453. Our data reveal extensive functional plasticity in the enteroinsular axis via induction of compensatory mechanisms that control nutrient-dependent regulation of insulin secretion.

A Study on a Design of Multiband Filters by Using Frequency Mapping Operation

A unified design method for multiband filters using a frequency mapping approach in the classical filter design is proposed. It has previously been reported that dual band bandpass and band elimination mapping approaches are obtained by applying the bandpass or band elimination mapping twice. In this study, we examine the variation of the filter characteristics by repeating the frequency mapping, and we have found that the frequency mapping for power-of-two bands can be obtained for the filter design. We have also confirmed that not only the mapping for the power-of-two bands but the mapping for arbitrary bands including odd number bands can be obtained. The present study has demonstrated that the filter design method by using the proposed frequency mapping is very effective for the multiband filter design.