In recent years, increased longevity of the Danish population has resulted in a growing segment with age-related and chronic health conditions. This, together with a general increase in the demand on ...the services of doctors, has augmented the role of pharmacies in the provision of healthcare services. In Denmark, a variety of pharmacy services has been developed, evaluated and implemented since the introduction of pharmaceutical care. The services are aimed at the person responsible for administering the medicine e.g. the patient themselves or care workers, thereby supporting medication safety. The services available have been developed, evaluated and implemented in collaboration between community pharmacies, the Danish Association of Pharmacies, the Danish College of Pharmacy Practice and international collaborators. In this commentary we present an overview of the available pharmacy service, the contents of each service, remuneration and the scientific evidence behind each service. The commentary covers: Inhaler Technique Assessment Service; New Medicines Service; Medication Review; and Medication Safety in Residential Facilities.
Peripheral pain pathways are activated by a range of stimuli. We used diphtheria toxin to kill all mouse postmitotic sensory neurons expressing the sodium channel Nav1.8. Mice showed normal motor ...activity and low-threshold mechanical and acute noxious heat responses but did not respond to noxious mechanical pressure or cold. They also showed a loss of enhanced pain responses and spontaneous pain behavior upon treatment with inflammatory insults. In contrast, nerve injury led to heightened pain sensitivity to thermal and mechanical stimuli indistinguishable from that seen with normal littermates. Pain behavior correlates well with central input from sensory neurons measured electrophysiologically in vivo. These data demonstrate that Nav1.8-expressing neurons are essential for mechanical, cold, and inflammatory pain but not for neuropathic pain or heat sensing.
Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain ...with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene
SCN9A, which encodes hNa
v1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na
v1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in
SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.
A medication review is a possibility to assess and optimise a patient's medicine. A model that includes a medication review and a follow-up seem to provide the best results. However, it is not known ...whether specific subgroups of patients benefit more from a medication review than others.
This literature review summarises the evidence that is available on which patient subgroups exist positive outcomes from a medication review carried out in a primary care setting.
We performed a PICO analysis to identify keywords for setting, medication review and effect. We then conducted a search using the PubMed database (2004 to 2019) to identify studies relevant for our investigation. A screening process was carried out based on either title or abstract, and any study that matched the aim and inclusion criteria was included. All matching studies were obtained and read, and were included if they met predefined criteria such as study design, medication review and primary care. The studies were divided into subgroups. First, each subgroup was divided according to the studies' own definition. Secondly, each subgroup was allocated as either risk patients if the subgroup described a specific patient subgroup or risk medication, if the subgroup was defined as using a specific type of medication. This was done after discussion in the author group.
28 studies from a total of 935 studies were included. Identified studies were divided into either risk patients; frail, recently discharged or multimorbid patients, or risk medication; heart medication, antithrombotic medication, blood pressure lowering medication, antidiabetic medication, anti-Parkinson medication or medication increasing the risk of falls. The subgroups identified from a medication review in primary care were defined as being frail, recently discharged from hospital or multimorbid (risk patients), or defined as patients using anticoagulant or blood pressure lowering medication (risk medication). Most of the medication reviews in the studies that showed an economic effect included at least one follow-up and were delivered by a pharmacist.
The literature review demonstrates that medication reviews delivered by pharmacists to specific subgroups of patients are a way of optimising the economic effect of medication reviews in primary care. This is obtained by reducing health-related costs or the number of contacts with primary or secondary health care services.
To examine the role of small RNAs in peripheral pain pathways, we deleted the enzyme Dicer in mouse postmitotic damage-sensing neurons. We used a Nav1.8-Cre mouse to target those nociceptors ...important for inflammatory pain. The conditional null mice were healthy with a normal number of sensory neurons and normal acute pain thresholds. Behavioral studies showed that inflammatory pain was attenuated or abolished. Inflammatory mediators failed to enhance excitability of Nav1.8+ sensory neurons from null mutant mice. Acute noxious input into the dorsal horn of the spinal cord was apparently normal, but the increased input associated with inflammatory pain measured using c-Fos staining was diminished. Microarray and quantitative real-time reverse-transcription PCR (qRT-PCR) analysis showed that Dicer deletion lead to the upregulation of many broadly expressed mRNA transcripts in dorsal root ganglia. By contrast, nociceptor-associated mRNA transcripts (e.g., Nav1.8, P2xr3, and Runx-1) were downregulated, resulting in lower levels of protein and functional expression. qRT-PCR analysis also showed lowered levels of expression of nociceptor-specific pre-mRNA transcripts. MicroRNA microarray and deep sequencing identified known and novel nociceptor microRNAs in mouse Nav1.8+ sensory neurons that may regulate nociceptor gene expression.
The excitatory amino acid transporters (EAATs) are expressed throughout the central nervous system, where they are responsible for the reuptake of the excitatory neurotransmitter (S)-glutamate (Glu). ...Recently, we have reported the discovery of the first subtype selective EAAT1 inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) (1b) and presented an introductory structure−activity relationship (SAR) study. Here, we present a detailed SAR by the design, synthesis, and pharmacological evaluation of analogues 1g−1t. By comparison of potencies of 1b, 1h, and 1i versus 1j, it is evident that potency is largely influenced by the chemical nature of the R1 substituent. The study also demonstrates that any chemical change of the functional groups or a change to the parental scaffold results in the complete loss of inhibitory activity of the compounds at EAAT1. Finally, a bioavailability study of UCPH-101 determined the half-life to be 30 min in serum (rats) but also that it was not able to penetrate the blood−brain barrier to any significant degree.
In the present study, the mechanism of action and molecular basis for the activity of the first class of selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its ...rodent ortholog GLAST are elucidated. The previously reported specificity of UCPH-101 and UCPH-102 for EAAT1 over EAAT2 and EAAT3 is demonstrated to extend to the EAAT4 and EAAT5 subtypes as well. Interestingly, brief exposure to UCPH-101 induces a long-lasting inactive state of EAAT1, whereas the inhibition exerted by closely related analogs is substantially more reversible in nature. In agreement with this, the kinetic properties of UCPH-101 unblocking of the transporter are considerably slower than those of UCPH-102. UCPH-101 exhibits noncompetitive inhibition of EAAT1, and its binding site in GLAST has been delineated in an elaborate mutagenesis study. Substitutions of several residues in TM3, TM4c, and TM7a of GLAST have detrimental effects on the inhibitory potency and/or efficacy of UCPH-101 while not affecting the pharmacological properties of (S)-glutamate or the competitive EAAT inhibitor TBOA significantly. Hence, UCPH-101 is proposed to target a predominantly hydrophobic crevice in the "trimerization domain" of the GLAST monomer, and the inhibitor is demonstrated to inhibit the uptake through the monomer that it binds to exclusively and not to affect substrate translocation through the other monomers in the GLAST trimer. The allosteric mode of UCPH-101 inhibition underlines the functional importance of the trimerization domain of the EAAT and demonstrates the feasibility of modulating transporter function through ligand binding to regions distant from its "transport domain."
The excitatory amino acid transporters (EAATs) play a pivotal role in regulating the synaptic concentration of glutamate in the mammalian central nervous system. To date, five different subtypes have ...been identified, named EAAT15 in humans (and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5, respectively, in rodents). Recently, we have published and presented a structure–activity relationship (SAR) study of a novel class of selective inhibitors of EAAT1 (and GLAST), with the analogs UCPH-101 (IC50=0.66μM) and UCPH-102 (IC50=0.43μM) being the most potent inhibitors in the series. In this paper, we present the design, synthesis and pharmacological evaluation of six coumarin-based fluorescent analogs of UCPH-101/102 as subtype-selective inhibitors at EAAT1. Analogs 1114 failed to inhibit EAAT1 function (IC50 values >300μM), whereas analogs 15 and UCPH-102F inhibited EAAT1 with IC50 values in the medium micromolar range (17μM and 14μM, respectively). Under physiological pH no fluorescence was observed for analog 15, while a bright blue fluorescence emission was observed for analog UCPH-102F. Regrettably, under confocal laser scanning microscopy selective visualization of expression of EAAT1 over EAAT3 was not possible due to nonspecific binding of UCPH-102F.
To graduate, pharmacy technician students write a project in their third year. They choose between six elective courses, and work with a subject related to their education and everyday practice at ...community or hospital pharmacies. In this article, we report the mapping of third-year project themes and provide an overview of the challenges that COVID-19 pandemic restrictions have had on completing the projects. On the basis of all project titles, a list of themes was generated and described before all projects were allocated to one of the themes. Challenges experienced due to the COVID-19 pandemic were investigated from an analytical workshop where supervisors discussed their experience with supervising students throughout the completion of the projects. In total, 140 projects were included and thematised into eight themes: advanced pharmacy services, digital patient support, organisation and collaboration, handling of medicine, automated dose dispensing, medication counselling in community pharmacy, hospital pharmacy, and others, covering all six elective courses. The COVID-19 pandemic affected students' possibilities to collect data from either physical interviews or observations. The challenges prompted both constructive and creative discussions between students and supervisors to find ways to complete the projects, and required flexibility from all those involved: students, supervisors, community pharmacies, and hospital pharmacies. In conclusion, all students managed to complete their third-year project at a similar level of achievement statistically compared to average grades for the previous six years (2016-2020).
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