Anti-TNF-α therapies for the treatment of Crohn’s disease: the past,present and future

Introduction: Anti-TNF-α therapy is a novel approach that has transformed the way moderate-to-severe Crohn’s disease (CD) is treated and has significantly improved clinical outcomes of patients with enhanced remission induction and maintenance efficacies. As a result, anti-TNF-α agents have become the primary cost driver in the treatment of CD, as the frequency of hospitalizations and surgical interventions have been drastically reduced.

Areas Covered: In the review, the authors cover current anti-TNF-α treatments for CD including efficacy, mechanisms of action, pharmacokinetics and safety. In addition, the authors discuss future anti-TNF-α agents currently in the development pipeline including biosimilars, golimumab, oral AVX-470, TNF-α-kinoid vaccine, and non-biologic HMPL-004.

Expert opinion: While new therapeutics are in the pipeline like anti-integrin and anti-interleukin therapeutics, anti-TNF-α therapy remains at the forefront of CD treatment due to its long-term efficacy and safety profiles. The next horizon for new anti-TNF-α agents is biosimilars, which offer comparable safety and effectiveness to the originator molecules. Biosimilars promise to expand accessibility to anti-TNF-α therapy while significantly reducing the cost burden to patients and healthcare systems.     

Psychoneurendocrinology: a science of the past or a new pathway for the future?

Psychoneuroendocrinology is a branch of neuroscience that developed in the beginning of the last century, which investigates the possibility of a cause-effect link between endocrinopathies and mental disorders - with these studies ending in negative results. Psychoneuroendocrinology was then used as a methodological approach for the investigation of neurotransmitter function, on the basis of the observation that neurotransmitters regulate neurohormone and peripheral hormone secretions. Data were obtained for hypothalamic noradrenergic, serotoninergic, dopaminergic, gabaergic and acetylcholinergic functions, which could not be automatically extended to higher brain centers whose impairments might be etiopathogenetically involved in the development of mental disorders. Future studies should focus on new methodological approaches to brain biochemistry, on investigation of genetic, molecular biology, brain imaging, psychoneuroimmunoendocrinology, neuropeptide and neurosteroid secretion in relation to brain endocrine function in mental diseases.     

Improving the performance of Drug and Therapeutics Committees in hospitals – a quasi-experimental study in Laos

Background and objectives Drug and Therapeutics Committees (DTCs), which are essential for ensuring the rational use of drugs (RUD) in hospitals, have recently been established in Laos. Sub-optimal performance had been reported. The aims of this study were to determine those factors in the working environment that relate to DTC performance in Lao hospitals and evaluate whether DTC performance could be improved through an educational intervention utilizing auditing and feedback targeted towards DTC members. Methods This was a quasi-experimental (before and after) study. Two central and seven provincial hospitals and the DTC members from these hospitals participated in the study. Performance of the DTCs was assessed by means of specifically developed indicators on structure and process combined with indicators for RUD and adherence to Standard Treatment Guidelines (STG). Data were collected for a 3-month period at baseline and for three consecutive periods thereafter. The results of the first three data collections were shared and discussed with the DTC members during feedback sessions. The DTC members were also interviewed in order to identify factors they thought may have an impact on DTC performance. Results Following the intervention, there was a significant improvement in the overall score for DTC performance (p<0.001) and, in particular, in general activity and feedback and drug information to staff. The STG scores also improved (p<0.01). Interviews indicated that one negative factor was the experience of the DTC members being overloaded with other work, resulting in DTC meetings being held irregularly and drawing poor attendance. Conclusion Continuous self-monitoring of performance by means of indicators, followed by feedback discussions, is suggested the means of improving the work of the DTC.     

Drug discovery for heart failure: a new era or the end of the pipeline?

Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of beta-blockers and antagonists of the renin-angiotensin system, there is still a major unmet need for better therapies for many patients with heart failure. However, disappointment related to late-stage clinical failures of a number of novel agents, including endothelin antagonists and tumour-necrosis factor blockers, has reduced the impetus of drug development in this field. Here, we review possible targets for heart failure therapy that have emerged from recent progress in our understanding of the underlying disease mechanisms, and highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.     

What knowledge and skills are essential for specialists in Clinical Pharmacology and Therapeutics? Results of a Delphi study

AIMS: To identify the knowledge and skills that should be considered essential for specialists in Clinical Pharmacology and Therapeutics (CPT) with a commitment to the National Health Service (NHS). METHODS: A Delphi study using a sample of current specialists. RESULTS: Members of the expert panel (20 in all, representative of the Clinical Section membership) identified 78 statements for consideration, in four domains (core of knowledge, therapeutic skills, educative skills, and investigative skills), of which 58 (74.4%) were accepted by more than two-thirds of respondents. Of these, 35 were knowledge items, whereas 23 were skills (11 therapeutic, 4 educative and 8 investigative). The large majority (79.3%) of these statements were endorsed by at least four out of five panel members. CONCLUSIONS: Despite the varied work patterns and responsibilities of specialists in CPT, it is possible to identify a core of knowledge and skill that most consider essential for the delivery of their commitment to the NHS. The findings will provide NHS Trusts with a clear idea of what they can expect from these specialists, and will act as a checklist for specialists themselves to direct their Continuing Professional Development within the consultant appraisal process. The results also describe a curriculum for continuing education in CPT, which the BPS Clinical Section can use to develop information resources and training opportunities.     

Protein–protein interaction modulator drug discovery: past efforts and future opportunities using a rich source of low- and high-throughput screening assays

Introduction: Historically, small-molecule drug discovery projects have largely focused on the G-protein-coupled receptor, ion-channel and enzyme target classes. More recently, there have been successes demonstrating that protein–protein interactions (PPIs) can be targeted by small-molecules and that this strategy has the potential to provide appropriate specificity and selectivity. However, a disadvantage is that compounds that modulate PPIs are often associated with relatively weak affinities as the targeted interaction surfaces are often relatively large. Moreover, from a small-molecule screening perspective, a large proportion of the initial screening Hits are often false positives and these need to be identified and excluded in order to focus on genuine modulators of the PPI being investigated.

Areas covered: The authors review previous efforts on PPI modulator drug discovery. Furthermore, they review assays that can be employed in small-molecule screening and/or Hit validation. The PPI assays are categorized as: i) low-throughput target-based biochemical assays, which are primarily employed for Hit validation at the post-screening stage; ii) high-throughput target-based biochemical assays that are suitable for screening campaigns; and iii) cell-based assays, which are suitable for high-throughput screening campaigns and/or Hit validation.

Expert opinion: Modulating the interaction of PPIs offers the potential to develop novel drugs to treat a wide range of diseases. New assay technologies are continually being developed and it is anticipated that these will be able to be directly used for small-molecule screening campaigns in the future.     

Role of Drug – Drug Interactions in the Efficacy and Safety of Clarithromycin Treatment for Helicobacter Pylori Eradication

Pharmaceutical Chemistry Journal - Current risks from resistance, adverse drug reactions, and drug – drug interactions of clarithromycin used as a component of Helicobacter pylori eradication...     

Advances in the study of drug metabolism – symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX)

Abstract

The 12th International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28 to 31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the “Advances in the Study of Drug Metabolism” symposium, as it engaged attendees with diverse backgrounds. This session covered a wide range of current topics in drug metabolism research including predicting sites and routes of metabolism, metabolite identification, ligand docking, and medicinal and natural products chemistry, and highlighted approaches complemented by computational modeling. In silico tools have been increasingly applied in both academic and industrial settings, alongside traditional and evolving in vitro techniques, to strengthen and streamline pharmaceutical research. Approaches such as quantum mechanics simulations facilitate understanding of reaction energetics toward prediction of routes and sites of drug metabolism. Furthermore, in tandem with crystallographic and orthogonal wet lab techniques for structural validation of drug metabolizing enzymes, in silico models can aid understanding of substrate recognition by particular enzymes, identify metabolic soft spots and predict toxic metabolites for improved molecular design. Of note, integration of chemical synthesis and biosynthesis using natural products remains an important approach for identifying new chemical scaffolds in drug discovery. These subjects, compiled by the symposium organizers, presenters, and the ISSX New Investigators Group, are discussed in this review.     

The use of national reimbursement reports to support formulary decisions of the hospital’s Drug and Therapeutics Committee: a comparative analysis

International Journal of Clinical Pharmacy - Background New therapies that do not reach patients in need, have not achieved their goal. Drug and Therapeutics Committees in hospitals ensure access...     

Combination Nanopreparations of a Novel Proapoptotic Drug – NCL-240, TRAIL and siRNA

Purpose

To develop a multifunctional nanoparticle system carrying a combination of pro-apoptotic drug, NCL-240, TRAIL [tumor necrosis factor-α (TNF-α)-related apoptosis-inducing ligand] and anti-survivin siRNA and to test the combination preparation for anti-cancer effects in different cancer cells.

Methods

Polyethylene glycol-phosphoethanolamine (PEG-PE) – based polymeric micelles were prepared carrying NCL-240. These micelles were used in combination with TRAIL-conjugated micelles and anti-survivin siRNA-S-S-PE containing micelles. All the micelles were characterized for size, zeta potential, and drug encapsulation efficiency. Different cancer cells were used to study the cytotoxicity potential of the individual as well as the combination formulations. Other cell based assays included cellular association studies of transferrin-targeted NCL-240 micelles and study of cellular survivin protein downregulation by anti-survivin siRNA-S-S-PE containing micelles.

Results

NCL-240 micelles and the combination NCL-240/TRAIL micelles significantly increased cytotoxicity in the resistant strains of SKOV-3, MCF-7 and A549 as compared to free drugs or single drug formulations. The NCL-240/TRAIL micelles were also more effective in NCI/ADR-RES cancer cell spheroids. Anti-survivin siRNA micelles alone displayed a dose-dependent reduction in survivin protein levels in A2780 cells. Treatment with NCL-240/TRAIL after pre-incubation with anti-survivin siRNA inhibited cancer cell proliferation. Additionally, a single multifunctional system composed of NCL-240/TRAIL/siRNA PM also had significant cytotoxic effects in vitro in multiple cell lines.

Conclusion

These results demonstrate the efficacy of a combination of small-molecule PI3K inhibitors, TRAIL, and siRNA delivered by micellar preparations in multiple cancer cell lines.

     

Physiologically Based Pharmacokinetic Modeling of Fimasartan,Amlodipine, and Hydrochlorothiazide for the Investigation of Drug–Drug Interaction Potentials

Purpose

To build a physiologically based pharmacokinetic (PBPK) model for fimasartan, amlodipine, and hydrochlorothiazide, and to investigate the drug–drug interaction (DDI) potentials.

Methods

The PBPK model of each drug was developed using Simcyp software (Version 15.0), based on the information obtained from literature sources and in vitro studies. The predictive performance of the model was assessed by comparing the predicted PK profiles and parameters with the observed data collected from healthy subjects after multiple oral doses of fimasartan, amlodipine, and hydrochlorothiazide. The DDI potentials after co-administration of three drugs were simulated using the final model.

Results

The predicted-to-observed ratios of all the pharmacokinetic parameters met the acceptance criterion. The PBPK model predicted no significant DDI when fimasartan was co-administered with amlodipine or hydrochlorothiazide, which is consistent with the observed clinical data. In the simulation of DDI at steady-state after co-administration of three drugs, the model predicted that fimasartan exposure would be increased by ~24.5%, while no changes were expected for the exposures of amlodipine and hydrochlorothiazide.

Conclusions

The developed PBPK model adequately predicted the pharmacokinetics of fimasartan, amlodipine, and hydrochlorothiazide, suggesting that the model can be used to further investigate the DDI potential of each drug.

     

Abstracts of the 84th Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) and the 20th Annual Meeting of the Association of the Clinical Pharmacology Germany (VKliPha) With contribution of the Arbeitsgemeinschaft für Angewandte Humanpharmakologie e. V. (AGAH)

Naunyn-Schmiedeberg's Archives of Pharmacology -     

Abstracts of the 83rd Annual Meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT) and the 19th Annual Meeting of the Association of the Clinical Pharmacology Germany (VKliPha) With contribution of the Arbeitsgemeinschaft für Angewandte Humanpharmakologie e. V. (AGAH)

Naunyn-Schmiedeberg's Archives of Pharmacology -     

The discovery and development of vilazodone for the treatment of depression: a novel antidepressant or simply another SSRI?

Introduction: Vilazodone is the newest serotonergic antidepressant to be approved by the FDA for the treatment of major depressive disorder (MDD). Vilazodone is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT_1A receptor partial agonist. It was originally designed based on the premise that negative feedback circuitry mediated through somatodendritic 5-HT₁ autoreceptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. Therefore, the combination of SSRI with 5-HT_1A receptor agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments.

Areas covered: This review provides the history and preclinical development of vilazodone, highlighting the available data on its putative mechanism of action, potential clinical profile and possible areas for differentiation. These preclinical hypotheses will be contextualised with an overview of the key findings from the current clinic data on vilazodone.

Expert opinion: Preclinical data packages on vilazodone have clearly demonstrated its SSRI activity. In isolated in vitro systems, 5-HT_1A receptor agonism has been demonstrated, but the recapitulation of this activity in vivo has been inconclusive. This uncertainty of its in vivo profile has largely translated to the clinical scenario with efficacy and adverse event profiles being similar to that seen with SSRIs in MDD. More in-depth evaluation of the two Phase III studies have also provided some early evidence of differentiation on onset of therapeutic benefit, anxiety measures and improvements in sexual function. Further evaluation of MDD and anxiety patient outcomes is essential to demonstrate if vilazodone is truly a novel therapeutic.