Blood–brain barrier models and their relevance for a successful development of CNS drug delivery systems: A review

During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood–brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood–brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood–brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood–brain barrier is also discussed.     

Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure

Phosphodiesterase-5 (PDE5) inhibitors have been approved for the treatment of erectile dysfunction and pulmonary hypertension, but enthusiasm on discovery of PDE5 inhibitors continues for their potential new applications. Reported here is discovery of a series of new PDE5 inhibitors by structure-based design, molecular docking, chemical synthesis, and enzymatic characterization. The best compound, 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one (57), has an IC₅₀ of 17 nM against the PDE5 catalytic domain and good selectivity over other PDE families. The crystal structure of the PDE5 catalytic domain in complex with 57 was determined at 2 Å resolution and showed that 57 occupies the same pocket as other PDE5 inhibitors, but has a different binding pattern in detail. On the basis of the binding pattern of 57, a novel scaffold can be proposed as a candidate of PDE inhibitors.     

Structure-Activity Relationship Studies of CNS Agents,Part 25: 4,6-Di(heteroaryl)-2-(N-methylpiperazino)pyrimidines as New,Potent 5-HT2A Receptor Ligands: A Verification of the Topographic Model

A series of new 4,6-di(heteroaryl)pyrimidines containing an N-methylpiperazino group ( 6 – 13 ) or an ethylenediamine chain ( 15 – 20 ) in position 2 were synthesized and their 5-HT_1A and 5-HT_2A receptor affinities were determined. It was shown that the substituent effects on the 5-HT_2A affinity are additive and could be described quantitatively. In a behavioral model it was also demonstrated that 6 – 11 are 5-HT_2A receptor antagonists. The molecular modelling results suggested that the distances between the basic nitrogen atom and the two aromatic centers (d₁ = 5.2?8.4 Å, d₂ = 5.7?8.5 Å, and d₃ = 4.6?7.3 Å) define the molecular topography of the 5-HT_2A receptor antagonists under study.     

Subcutaneously Administered Recombinant Human Interleukin-2 and Interferon Alfa-2a for Advanced Breast Cancer: A Phase II study of the Cancer and Leukemia Group B (CALGB 9041)

New and more effective treatments are needed for metastatic breast cancer. This study aimed to determine the effectiveness of a combination of subcutaneously administered recombinant human interleukin-2 (rIL-2), 1.5 MU/m(2) for 5 consecutive days repeated for 3 weeks, and interferon alpha-2a (IFN), 7.5 MU/m(2), administered subcutaneously three times per week. Women who had previously received 1-2 prior chemotherapy regimens for measurable inoperable, recurrent, or metastatic breast cancer were eligible. Of 40 patients accrued to the study, 32 were evaluable for response assessment. Toxicities were frequent but manageable. The most common grade 3 and 4 toxicities were lymphopenia (17%) and malaise/fatigue (24%). There were no complete responses, one partial response (3%), and six patients with stable disease (19%). Of the seven patients with partial response or stable disease, all had tumors that expressed hormone receptors. The median survival was 8.9 months and all patients have died. Good performance status was the most important predictor of survival. In this group of women with metastatic breast cancer, the overall prognosis was poor. This combination of rIL-2 and IFN was ineffective.     

Effect of the anticoagulant ethylenediamine tetra-acetic acid (EDTA) on the estimation of pharmacokinetic parameters: A case study with tigecycline and ciprofloxacin

Tigecycline and ciprofloxacin were employed as the model compounds to study the effect of the anticoagulant ethylenediamine tetra-acetic acid (EDTA), which is used during plasma sample preparations, on the determination of pharmacokinetic parameters. The pharmacokinetic parameters were determined in rats following intravenous infusion with blood samples collected in serum separators, with either EDTA- or heparin-coated tubes. The blood-to-plasma (B:P) partition ratio and plasma protein binding were determined in vitro in rat or human blood collected in either EDTA- or heparin-coated tubes. Drug concentrations were quantified by liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS) analysis. In tigecycline-treated rats drug concentrations were twofold lower in EDTA plasma, leading to a twofold lower area under plasma concentration–time curve (AUC) and twofold higher plasma clearance values as compared with those obtained from heparin plasma. No differences were noted in the pharmacokinetic parameters obtained from heparin-treated plasma versus serum. The B:P partition ratio and unbound fraction for tigecycline were significantly higher in EDTA-treated blood. When normalized to the B:P partition ratios, the tigecycline blood clearance values were identical between samples collected in EDTA- or heparin-coated tubes. Similar but smaller differences were observed for ciprofloxacin. It was concluded that EDTA might compete with tigecycline and ciprofloxacin for chelating metal ions and thus affect drug partition between blood and plasma compartments, leading to inaccurate measurement of pharmacokinetic parameters in plasma.     

Morphine-like discriminative stimulus effects of opioid peptides: possible modulatory role ofd-Ala2-d-Leu5-enkephalin (DADL) and dynorphin A(1-13)

The role of the different opioid receptors was studied in rats trained to discriminate SC injections of 3.0 mg/kg morphine from saline by tests for generalization to graded doses of morphine and receptor-selective peptides administered into the lateral cerebral ventricle. Dose-dependent morphine-like stimulus effects were produced over a wide range of doses (0.001–30 g), depending upon ligand and animal, by morphine, by themu-selective peptides DAGO[d-Ala²-NMePhe⁴-Gly(ol)-enkephalin] and FK33824[d-Ala²,NMePhe⁴-Met(O)⁵-(ol)-enkephalin], and by thedelta-selective peptide, DADL[d-Ala²,d-Leu⁵enkephalin]. The order of relative potency of these substances was: FK33824>DAGO>morphine>DADL. In contrast, DPLPE[d-Pen²,l-Pen⁵)enkephalin], which has much greaterdelta receptor selectivity than does DADL, and dynorphin A(1-13) (0.1–10 g), akappa-receptor agonist, engendered choice responding appropriate for saline. When 1.0 g DADL, a dose lacking morphine-like discriminative effects, was administered concurrently with SC morphine, the stimulus effects of morphine were potentiated. Concurrent administration of 10 g dynorphin A(1-13) and morphine attenuated the stimulus effects of morphine inconsistently. These results support previous findings thatmu-opioid receptors are of primary importance in mediating the morphine-like discriminative effects of opioid peptides. They also suggest that morphine-like discriminative effects can be modulated by other types of opioid receptors.     

Targeting regulated cell death (RCD) with small-molecule compounds in cancer therapy: A revisited review of apoptosis,autophagy-dependent cell death and necroptosis

Evasion of regulated cell death (RCD), mainly referring to apoptosis, autophagy-dependent cell death, necroptosis, and other subroutines, is one of the well-established hallmarks of cancer cells. Accumulating evidence has revealed several small-molecule compounds that target different subroutines of RCD in cancer therapy. In this review, we summarize key pathways of apoptosis, autophagy-dependent cell death and necroptosis in cancer, and describe small-molecule compounds that target these pathways and have potential as therapeutics. These inspiring findings light the way towards the discovery of more ‘magic bullets’ that could work individually or cooperatively to target precisely the three RCD subroutines and so improve cancer treatment.     

Experiences of key stakeholders with the implementation of medication reviews in community pharmacies: A systematic review using the Consolidated Framework for Implementation Research (CFIR)

BackgroundThough medication reviews have shown positive patient outcomes, they are still not widely implemented in community pharmacies. Published reviews on their implementation often include several other pharmacy services, making them non-specific. Using the Consolidated Framework for Implementation Research (CFIR) to focus solely on the experiences of different stakeholders with the implementation of medication reviews will help to better understand relevant facilitators and barriers.ObjectivesTo critically appraise, synthesise and present the available evidence on experiences of key stakeholders with the implementation of medication reviews and to identify barriers and facilitators to its implementation in community pharmacies.MethodsA systematic literature search was conducted in four databases for studies published in English, Spanish or German. Key search terms included: implementation, pharmac*, medication review, facilitator, barrier. Study selection, quality assessment and data extraction were performed by two independent reviewers. Findings were mapped directly against the constructs of the CFIR.ResultsOut of 924 retrieved records 24 articles from 9 countries met the inclusion criteria. Key facilitators identified included pharmacists' openness to practice change and a high degree of patient satisfaction post medication review. Attracting patients to the service was stated as challenging due to an unawareness of the scope and potential benefit of a medication review. The dominant barrier was inadequate remuneration, as it impacted all additional resourcing and ultimately the viability of the service. Further barriers included difficult professional relationships with doctors and little mandate from health authorities. Most reports were from the employed pharmacists’ perspective and concerned the inner setting, other perspectives were under-reported.ConclusionsResults of this systematic review illustrate different stakeholders' experiences and add to the understanding of challenges in the implementation process. Nevertheless, findings also highlight how scarce reporting of external stakeholders’ views is and that filling this gap can unveil hidden barriers and facilitators.RegistrationPROSPERO register (CRD 42019122836)     

Short-term black tea intake modulates the excretion of urinary mutagens in rats treated with 2-amino-3-methylimidazo-[4,5-<Emphasis Type="Italic">f</Emphasis>]quinoline (IQ): role of CYP1A2 upregulation

Rats were exposed to black tea (2.5% w/v) as their sole drinking liquid for either 1 day or 1 month, while controls were maintained on water. After this treatment period, all animals received a single oral dose IQ (2-amino-3-methylimidazo-[4,5-f]quinoline), and urine was collected for 48 h. Mutagenic activity of the urine was determined in the Ames test in the presence and absence of an activation system. The excretion of direct-acting mutagens was markedly reduced following tea intake, and was more pronounced after the 1-day treatment. Similarly, both tea treatments suppressed the excretion of indirect-acting mutagens. Furthermore, both tea treatments induced hepatic CYP1A2 activity and expression, but cytosolic glutathione S-transferase activity was only modestly induced in the group of animals receiving tea for 1 day, and only when DCNB (1,2-dichloro-4-nitrobenzene) was used as substrate; glucuronosyl activity was elevated modestly only in the animals receiving the tea for a month. It is concluded that even short-term exposure to black tea is capable of influencing the metabolic fate of IQ, and this is most likely related to the upregulation of CYP1A2.