Dorsal horn volume loss and pain pathway changes in Cavalier King Charles Spaniels with syringomyelia, signs of pain, and phantom scratching.

ABSTRACT: Central neuropathic pain is a core clinical sign of syringomyelia in humans and Cavalier King Charles Spaniel (CKCS) dogs. This histopathological study used spinal cords from CKCS dogs with syringomyelia to investigate the following conditions: (1) whether specific structural cervical spinal cord entities involved in nociception were affected by loss of neuroparenchyma or other pathological changes in CKCS dogs with pain-related behaviour and phantom scratching, (2) whether pain-related behaviour or phantom scratching correlated with loss of a specific anatomical entity or upregulation of glia cells, and (3) whether syringomyelia-related lesions affected specific functional spinal cord units of nociception. Spinal cord segments C1-C8 from CKCS dogs with magnetic resonance imaging-confirmed syringomyelia and clinical signs of pain and phantom scratching (n = 8) were compared with those from CKCS dogs without syringomyelia (n = 4). Dogs with unilateral scratching (n = 7) had a volume loss ( P = 0.043) of the dorsal horn laminae I-III in the ipsilateral side compared with the contralateral dorsal horn. A clear pattern of ipsilateral changes in the dorsal root entry zone characterised by deafferentation and reorganization of first-order axons into deeper laminae was found in cases with lateralised scratching. Significant changes in cell number density were not found for astrocytes or microglia, suggesting that the dogs represented cases of end-stage syringomyelia and thus could not reveal astrogliosis and microgliosis, which may be involved in the early phases of syrinx development and phantom scratching. The present relationship between clinical findings and dorsal horn and pain pathway pathology in CKCS dogs suggests that these dogs may be of interest as a supplement to experimental model pain research.

Analysis of the Authorized Target Populations for Fixed Dose Combination Products Between 2000 and 2017 Reveals Discrepancies Between EMA's and FDA's Views on Initial Dual-Therapy.

BACKGROUND: A fixed dose combination (FDC) product containing two components can be authorized for the use in 3 conceptual scenarios (1) as substitution for a treatment regimen containing both components given separately (substitution therapy) or (2) as replacement for a treatment regimen where the patient currently receives one of the components (add-on therapy) or (3) initial treatment of patients naïve to both components (initial combination therapy). METHOD: Trends in European Medicine Agency (EMA) and Food and Drug Administration (FDA) approvals of FDC products for the 3 scenarios were explored by comparing the therapeutic indications retrieved from the EMA and FDA websites for FDCs approved between January 2000 and April 2017 within 5 selected therapeutic areas: type 2 diabetes mellitus (T2DM), asthma, chronic obstructive pulmonary disease, hypertension, and human immunodeficiency virus (HIV) infection. RESULT: Approval decisions between EMA and FDA were largely aligned for the substitution therapy and add-on therapy scenarios. Discrepancies were found for the initial combination therapy scenario. CONCLUSION: Since EMA and FDA rely on similar conceptional models when approving FDCs, the reasons behind this general disparity are not clear, but may be found in the lack of evidence from the registration studies. Sponsors and health authorities should work collaboratively on closing that gap.

Demonstrating Contribution of Components of Fixed-Dose Drug Combinations Through Longitudinal Exposure-Response Analysis.

Exposure-response (ER) modeling for fixed-dose combinations (FDC) has previously been found to have an inflated false positive rate (FP), i.e., observing a significant effect of FDC components when no true effect exists. Longitudinal exposure-response (LER) analysis utilizes the time course of the data and is valid for several clinical endpoints for FDCs. The aim of the study was to investigate if LER is applicable for the validation of FDCs by demonstrating the contribution of each component to the overall effect without inflation of FP rates. FP and FN rates associated with ER and LER analysis were investigated using stochastic simulation and estimation. Four hundred thirty-two scenarios with varying numbers of patients, duration, sampling frequency, dose distribution, design, and drug activity were analyzed using a range of linear, log-linear, and non-linear models to asses FP and FN rates. Lastly, the impact of the clinical trial parameters was investigated. LER analyses provided well-controlled FP rates of the expected 5% or less; however, in low information clinical trials consisting of 30 patients, 4 samples, and 20 days, LER analyses lead to inflated FN rates. Parameter investigation showed that when the clinical trial includes sufficient patients, duration, samples, and an appropriate trial design, the FN rates are in general below the expected 5% for LER analysis. Based on the results, LER analysis can be used for the validation of FDCs and fixed ratio drug combinations. The method constitutes a new avenue for providing evidence that demonstrates the contribution of each component to the overall clinical effect.

Glutamate transport system as a key constituent of glutamosome: Molecular pathology and pharmacological modulation in chronic pain.

Neural uptake of glutamate is executed by the structurally related members of the SLC1A family of solute transporters: GLAST/EAAT1, GLT-1/EAAT2, EAAC1/EAAT3, EAAT4, ASCT2. These plasma membrane proteins ensure supply of glutamate, aspartate and some neutral amino acids, including glutamine and cysteine, for synthetic, energetic and signaling purposes, whereas effective removal of glutamate from the synaptic cleft shapes excitatory neurotransmission and prevents glutamate toxicity. Glutamate transporters (GluTs) possess also receptor-like properties and can directly initiate signal transduction. GluTs are physically linked to other glutamate signaling-, transporting- and metabolizing molecules (e.g., glutamine transporters SNAT3 and ASCT2, glutamine synthetase, NMDA receptor, synaptic vesicles), as well as cellular machineries fueling the transmembrane transport of glutamate (e.g., ion gradient-generating Na/K-ATPase, glycolytic enzymes, mitochondrial membrane- and matrix proteins, glucose transporters). We designate this supramolecular functional assembly as 'glutamosome'. GluTs play important roles in the molecular pathology of chronic pain, due to the predominantly glutamatergic nature of nociceptive signaling in the spinal cord. Down-regulation of GluTs often precedes or occurs simultaneously with development of pain hypersensitivity. Pharmacological inhibition or gene knock-down of spinal GluTs can induce/aggravate pain, whereas enhancing expression of GluTs by viral gene transfer can mitigate chronic pain. Thus, functional up-regulation of GluTs is turning into a prospective pharmacotherapeutic approach for the management of chronic pain. A number of novel positive pharmacological regulators of GluTs, incl. pyridazine derivatives and ß-lactams, have recently been introduced. However, design and development of new analgesics based on this principle will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of the glutamate transport system in nociceptive circuits. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.

Body of evidence and approaches applied in the clinical development programme of fixed-dose combinations in the European Union from 2010 to 2016.

AIMS: To provide insights into the clinical development pathway for fixed-dose combinations (FDCs), to consider strategies, and to elucidate the path to approval by assessing the body of evidence, as summarized in the European Public Assessment Reports. METHODS: The main resource was the European Public Assessment Reports for 36 FDCs, which included 239 clinical trials with 157 514 patients. The analyses focused on how prior knowledge of the active substances or combination, use of pharmacokinetic-pharmacodynamic modelling, and clinical trial design choice impact the size and strategy of the clinical development programme. RESULTS: FDC products primarily comprised 2 previously approved components (21/36, 71%) and had only 1 approved combination (21/36, 71%). Utilizing previously approved active substances resulted in fewer clinical trials, arms and patients, but FDC doses studied in the clinical development programme. Furthermore, dose-finding trials were performed for less than half of FDCs consisting of 2 previously approved active substances. The standard approach to demonstrate contribution of active substances was through a factorial or single combination study. Finally, the use of pharmacokinetic modelling showed a significant decrease in the number of FDC doses studied. CONCLUSIONS: The field of FDCs seems to be on the rise, utilizing new molecular entities, prior knowledge and re-profiling drugs. However, a way to move FDC development forward might be through new regulatory and scientific paradigms, in which it is encouraged to utilize model-based approaches to develop FDCs with multiple dose levels and dose ratios for exposure-based treatment that will enable personalization.

Identifying Off-Label Prescriptions Through Data Mining in Danish Community Pharmacy Servers: An Exploratory Study on Desmopressin, Diclofenac, Fucidin, Mirtazapine and Quetiapine.

The term off-label use describes the prescription and administration of medicines outside of the terms for which it officially has been approved, including age, dose and indication. Off-label data can be generated from the Danish National Prescription Registry through combinations with diagnoses; however, the community pharmacy servers provide equal, local, albeit less data through a faster and less constrained collection process. The data collection for this exploratory study took place at five community pharmacies in Denmark. Five drugs were chosen for the investigation and collection of prescription data across a 2-year period. Off-label use by age was observed to be 1.9% for diclofenac, 1.7% for desmopressin and 2.3% for quetiapine. The percentages were based on total number of 3881, 925, 2712 prescriptions, respectively. Off-label monitored by dosage appeared to be 75% for quetiapine; by box label text analysis, off-label indication was found to be 10-15% and 15-23% for quetiapine and mirtazapine (from a total number of 3178 prescriptions), respectively. By route of administration where fucidin ointment was applied to the nose in 60 patients, 83% were prescribed off-label (non-dermatological). This exploratory study revealed that pharmacy servers represent a reliable and up-to-date source to collect a substantial amount of raw prescription data. The method gives straightforward and simple access to analysis of off-label use by age and dose, whereas it is possible but difficult to interpret off-label indications and route of administration from the box label text.

Glutamate Transport System as a Novel Therapeutic Target in Chronic Pain: Molecular Mechanisms and Pharmacology.

The vast majority of peripheral neurons sensing noxious stimuli and conducting pain signals to the dorsal horn of the spinal cord utilize glutamate as a chemical transmitter of excitation. High-affinity glutamate transporter subtypes GLAST/EAAT1, GLT1/EAAT2, EAAC1/EAAT3, and EAAT4, differentially expressed on sensory neurons, postsynaptic spinal interneurons, and neighboring glia, ensure fine modulation of glutamate neurotransmission in the spinal cord. The glutamate transport system seems to play important roles in molecular mechanisms underlying chronic pain and analgesia. Downregulation of glutamate transporters (GluTs) often precedes or occurs simultaneously with development of hypersensitivity to thermal or tactile stimuli in various models of chronic pain. Moreover, antisense knockdown or pharmacological inhibition of these membrane proteins can induce or aggravate pain. In contrast, upregulation of GluTs by positive pharmacological modulators or by viral gene transfer to the spinal cord can reverse the development of such pathological hypersensitivity. Furthermore, some multi-target drugs displaying analgesic properties (e.g., tricyclic antidepressant amitriptyline, riluzole, anticonvulsant valproate, tetracycline antibiotic minocycline, ß-lactam antibiotic ceftriaxone and its structural analog devoid of antibacterial activity, clavulanic acid) can significantly increase the spinal glutamate uptake. Thus, mounting evidence points at GluTs as prospective therapeutic target for chronic pain treatment. However, design and development of new analgesics based on the modulation of glutamate uptake will require more precise knowledge of molecular mechanisms underlying physiological or aberrant functioning of this transport system in the spinal cord.

A Paradigm Shift Towards Patient Involvement in Medicines Development and Regulatory Science: Workshop Proceedings and Commentary.

The Copenhagen Centre for Regulatory Science (CORS) and Biopeople at the University of Copenhagen held a workshop in May 2015 titled "Patient Involvement in Medicines Development and Approvals: A Paradigm Shift Towards True Patient Impact in Medicines Development and Regulatory Science" that acknowledged the importance of having patients more involved in the entire process of medicines research and development (R&D) and life cycle management. Four key stakeholders, representing patients, academia, industry, and regulatory authorities, each gave their view and perspective on the status and challenges of current patient involvement. From the 3 breakout sessions, it was concluded that patient-reported outcomes (ie, the report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else), was considered as an important tool when deciding endpoints. It was agreed that professionalization of the patient within medicine R&D to some extent would be necessary for obtaining influence. However, the industry should also seek to accommodate to the patient instead of waiting passively for patients to become educated. A much better organized and stronger involvement of patients was called for. However, this should not only rely on goodwill, but should preferably be implemented by legal requirements, so as to secure compliance by all stakeholders. An independent platform with the purpose of providing access to patient experience was proposed. A research and educational center such as CORS, which was founded on cross-sectorial and cross-disciplinary cooperation, is an example of an institution that could be a good starting point for hosting such a platform.

Detection of adverse drug reactions among ordinary users of liraglutide on the occasion of drug dispensing in the community pharmacy setting.

OBJECTIVES: Postmarketing studies of drugs forms an essential part of safety surveillance. In particular, this concerns new drugs as safety information of these by large rests on randomized clinical studies conducted on a limited number of subjects before licensing. Pharmacists in community pharmacies are in a unique position for detection of user experienced adverse drug reactions (ADRs) in relation to drug dispensing. The study reports from a research initiative exploring prompt and proactive ADR detection of liraglutide and reporting facilitated by pharmacy students undertaking internship in a community pharmacy in Denmark. METHODS: Nineteen pharmacy students undertaking regular 6 months' internship--eighth semester--in a Danish community pharmacy participated in the data collection. Before the data collection, students attended an interactive training seminar addressing ADRs in general, organ symptoms, diagnostic classification, and pharmacovigilance systems. Pharmacy students approached recurrent drug users purchasing liraglutide. Participating users were asked about experienced ADRs linked to liraglutide use. Reported ADRs were collected and analyzed. RESULTS: Sixty-two liraglutide users participated in the study, of whom, 38 reported 84 ADRs possibly linked to liraglutide usage. Nausea was by far the most reported ADR followed by decreased appetite, diarrhea, fatigue, and abdominal pain (upper). The reported ADRs are in accordance with previously reported ADRs. CONCLUSIONS: The study has demonstrated the feasibility of community pharmacy driven pharmacovigilance. The study supports the thesis that community pharmacists in the future may play a proactive and prominent role in patient-centered pharmacovigilance.

Pharmacy student driven detection of adverse drug reactions in the community pharmacy setting.

PURPOSE: Post-marketing safety studies of adverse drug reactions (ADRs) form an important part of pharmacovigilance. Countries having a formal pharmacovigilance system to a large extent rely on voluntary ADR reporting from health professionals through spontaneous report systems. The contribution of pharmacists in ADR reporting, although varies significantly among countries. Pharmacists in community pharmacies are in a unique position for detection of experienced ADRs by the drug users. The study reports from a study on community pharmacy internship students' proactive role in ADR detection through direct encountering and questioning with drug users. METHOD: Pharmacy students undertaking internship in a community pharmacy were approached. Thirteen students from nine community pharmacies participated in the project as data collectors. Prior to the study students attended an educational seminar focusing on ADR detection and reporting in general. Ibuprofen was chosen as the drug of study. Pharmacy students approached recurrent drug users purchasing the drug. Participating users were asked about experienced ADRs linked to ibuprofen use. Reported ADRs were collected and analysed. RESULTS: Hundred and twenty eight ibuprofen users participated in the study out of who thirty three reported forty five ADRs possibly linked to ibuprofen use. The reported ADRs followed earlier reported patterns of distribution with gastric pain showing up as the most commonly reported symptom followed by heartburn, nausea, diarrhoea and constipation. CONCLUSIONS: Through adequate training community pharmacy internship students get competencies and are capable of detecting and reporting ADRs through direct questions to drug users.