Abstract This article addresses the possibility to initiate Fixed Dose Combination (FDC) therapy in form of Xultophy without prior exposure to the individual active entities of the FDC in Type 2 Diabetic Mellitus (T2DM) patients. This study used real-world patient reported outcomes (PROs) measures to compare FDC product intended for the three therapies (initial therapy, add-on therapy and substitution therapy) tested under real-world clinical practice using community pharmacy setting. The collected Patient Reported Outcomes (PROs) during the real-world clinical practice might be compared to the PROs used under controlled clinical trial settings to support labelling claims, facilitate decision making and gain authority approval. It was found that the real-world data collected may give valuable data useful for both the authority and the physician’ decision when it comes to select the suitable treatment for the individual patient.

Background: Hydroxyurea (HU) is the most commonly used first-line cytoreductive treatment option for patients with myeloproliferative neoplasms (MPN) worldwide. However, increasing evidence on the efficacy and safety of pegylated interferon-alpha2 (IFNα) is emerging, and optimal first-line treatment is to be established. Aims: To compare the efficacy and safety of HU vs. low-dose IFNα in patients with MPN over five years. Methods: DALIAH (NCT01387763) was a randomized phase III trial of HU vs. IFNα in newly diagnosed or untreated patients with MPN (essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF), and primary myelofibrosis (PMF)). Patients > age 60 were randomized (1:1:1) to HU, IFNα-2a, or IFNα-2b whereas patients ≤ age 60 were randomized to IFNα-2a or IFNα-2b. The primary outcome was the JAK2V617F molecular response (MR) rate at 18, 36, and 60 months per 2009 European LeukemiaNetwork (ELN) (ET, PV, PreMF) or 2005 European Myelofibrosis Network (EUMNET) (PMF) criteria. Secondary outcomes included the complete clinicohematologic response (CHR) rate at 12 months. The JAK2V617F allele burden was measured using quantitative polymerase chain reaction (qPCR) on peripheral blood (assay sensitivity: 0.1%). Primary and secondary outcomes were compared between groups (HU vs. IFNα or HU vs. IFNα > 60 years) using Fisher's exact test (categorical variables) or Wilcoxon rank-sum test (continuous variables). Paired comparisons (within groups) were made using Wilcoxon signed-rank test. Serial JAK2V617F measurements were compared by unadjusted mixed-effects linear regression analysis. Results: We included 203 patients (ET: 73 (36%), PV: 89 (44%), PreMF: 16 (8%), and PMF: 25 (12%)) in the modified intention-to-treat (ITT) population. Baseline characteristics were well balanced except for median age (HU: 68 years vs. IFNα: 59 years, p<0.0001) ( Table 1). The MR rate by ITT analysis was similar between HU and IFNα (18 months: 19% vs. 21%, p=1.00; 36 months: 19% vs. 26%, p=0.64; 60 months: 23% vs. 24%, p=1.00) (Figure 1A). However, the JAK2V617F allele burden was significantly lower in the IFNα group at month 36 and beyond (Figure 1B) and the absolute median (IQR) change in JAK2V617F allele burden (baseline to 60 months) was greater with IFNα (-20% (-9;-49) vs. -7% (3;-15), p=0.0053) (Figure 1C). Two patients (IFNα: n=2) were in complete molecular remission (undetectable JAK2V617F) at 60 months. The CHR rate by ITT analysis was higher with HU at 18 months (58% vs. 38%, p=0.03) but similar at all other time points (12 months: 50% vs. 36%, p=0.21; 60 months: 24% vs. 22%, p=0.83) ( Figure 1D). A post hoc subgroup analysis comparing HU with IFNα > age 60 showed comparable efficacy results. Among patients remaining on treatment (per-protocol analysis), the MR and CHR rates were superior in the IFNα group compared to the HU group at 36 months and beyond. The MR and CHR rates (HU vs. IFNα) by per-protocol analysis were: MR at 36 months: 23% vs. 56%, p=0.01; MR at 48 months: 27% vs. 59%, p=0.02; MR at 60 months: 35% vs. 67%, p=0.03; CHR at 36 months: 33% vs. 67%, p=0.002; CHR at 60 months: 38% vs. 62%, p=0.05. Overall treatment discontinuation at 60 months was 60% (HU: 37% vs. IFNα: 65%, p=0.0019). The most common cause of treatment discontinuation was adverse events (HU: 6/38 (16%); IFNα: 71/165 (43%)). Adverse events ≥ grade 3 occurred in 46% (HU: 58% vs. IFNα: 45%, p=0.15). Nineteen major thrombotic events were reported in 16 patients (HU: 4 events in 4 patients; IFNα>60: 12 events in 10 patients; IFNα≤60: 3 events in 2 patients), corresponding to an incidence rate of 2.6 per 100 person-years for HU and 3.4 per 100 person-years for IFNα (IFNα>60: 6.2; IFNα≤60: 1.2). None of the patients transformed into secondary acute myeloid leukemia. Five patients died during follow-up (HU: 2; IFNα: 3). Bone marrow histologic remission rates at 36 and 60 months will be presented at the meeting. Conclusion: ITT analysis detected no significant difference in the MR or CHR rates between HU and IFNα with long-term treatment (5 years) among patients with MPN, reflecting a higher treatment discontinuation rate in the IFNα group (65%). Thus, using the per-protocol principle, the MR and CHR rates were superior in the IFNα group at 36 months and beyond.

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.

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.

Objective We aimed to assess the efficacy and benefit-risk profile of pregabalin (PGN) to reduce the clinical signs of central neuropathic pain (CNeP) as reflected by scratching episodes in dogs with symptomatic syringomyelia (SM). Study design Randomized, double-blind, placebo-controlled crossover study. Animals A total of 12 client-owned Cavalier King Charles Spaniels (age, 1.1-7.4 years, bodyweight, 8.2-10.8 kg) with magnetic resonance imaging-confirmed SM and clinical signs of CNeP. Methods Dogs were randomized to either PGN 150 mg or placebo for 25 days, followed by 48 hour washout period before crossover to the alternate phase of 25 days. The primary outcome was defined as number of scratching events during 10 minutes of video-recorded physical activity. Treatment effect was estimated using a generalized estimation equation model. Benefit-risk and quality of life assessments were obtained through owner interviews focusing on potential adverse events. Results The treatment effect estimate was an 84% (95% confidence interval = 75-89%) reduction in mean number of scratching events relative to baseline compared with placebo (p < 0.0001). Owner-assessed satisfactory quality of life was status quo and rated as 'good' or 'could not be better' in six/11 dogs and improved in four/11 dogs. The most prevalent adverse events were increased appetite in nine/12 dogs and transient ataxia in nine/12 dogs. There was one dog withdrawn by the owner 7 days after crossover to PGN owing to persistent ataxia. No dogs needed rescue analgesia during the trial. Conclusions and clinical relevance PGN is superior to placebo in the reduction of clinical signs of SM-related CNeP in dogs. At a dose range of 13-19 mg kg(-1) orally twice daily, the encountered adverse events were acceptable to all but one owner.

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.

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 β-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.

Neuropathic pain is a major incurable clinical problem resulting from peripheral nerve trauma or disease. A central mechanism is the reduced expression of the potassium chloride cotransporter 2 (KCC2) in dorsal horn neurons induced by brain-derived neurotrophic factor (BDNF), causing neuronal disinhibition within spinal nociceptive pathways. Here, we demonstrate how neurotensin receptor 2 (NTSR2) signaling impairs BDNF-induced spinal KCC2 down-regulation, showing how these two pathways converge to control the abnormal sensory response following peripheral nerve injury. We establish how sortilin regulates this convergence by scavenging neurotensin from binding to NTSR2, thus modulating its inhibitory effect on BDNF-mediated mechanical allodynia. Using sortilin-deficient mice or receptor inhibition by antibodies or a small-molecule antagonist, we lastly demonstrate that we are able to fully block BDNF-induced pain and alleviate injury-induced neuropathic pain, validating sortilin as a clinically relevant target.

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.

Human studies have demonstrated a correlation between noncoding polymorphisms of “the pain protective” haplotype in the GCH1 gene that encodes for GTP cyclohydrolase I (GTPCH1)—which leads to reduced tetrahydrobiopterin (BH4) production in cell systems—and a diminished perception of experimental and clinical pain. Here, we investigate whether heterozygous mutations in the GCH1 gene which lead to a profound BH4 reduction in patients with dopa-responsive dystonia (DRD) have any effect on pain sensitivity. The study includes an investigation of GCH1 -associated biomarkers and pain sensitivity in a cohort of 22 patients with DRD and 36 controls. The patients with DRD had, when compared with controls, significantly reduced levels of BH4, neopterin, biopterin, and GTPCH1 in their urine, blood, or cytokine-stimulated fibroblasts, but their pain response with respect to non-painful stimulation, (acute) stimulus-evoked pain, or pain response after capsaicin-induced sensitization was not significantly different. A family-specific cohort of 11 patients with DRD and 11 controls were included in this study. The patients with DRD were heterozygous for the pain protective haplotype in cis with the GCH1 disease-causing mutation, c.899T>C. No effect on pain perception was observed for this combined haplotype. In conclusion, a reduced concentration of BH4 is not sufficient to alter ongoing pain sensitivity or evoked pain responses.

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.

This commentary concerns a postgraduate education and training initiative within the pharmaceutical sciences with the purpose to inspire future course organizers. It reports on the experiences obtained from preparing and evaluating two blended learning courses organized under the European Modular Education and Training Programme SafeSciMET. The blended courses included an eLearning part, followed by a face-to-face part of 2.5 days involving interactive case studies, and an examination. The purpose was to reduce the time the students spent away from work and home by 2 days. The feedback from the students and teachers is presented.

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, β-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.

Neurons sensing noxious stimuli and conduct pain signals from periphery to the spinal cord are predominantly glutamatergic. Members of the SLC1A family of high-affinity glutamate transporters, GluTs (GLAST/EAAT1, GLT1 / EAAT2, EAAC1 / EAAT3, and EAAT4) are differentially expressed in sensory neurons and surrounding glial cells. These plasma membrane proteins together with glutamate/cystine exchanger, xCT, are responsible for fine tuning of glutamate concentrations at glutamate receptors and, thus, modulation of excitatory signalling in the spinal cord. Several compounds, believed to affect high-affinity glutamate transport system, including therapeutically promising beta-lactams, have been examined in an in vivo model of neuropathic pain. Both pain behavior and glutamate transporter expression have been investigated in this model at various time-points. For the first time, changes in the expression of rare splice variants of glial glutamate transporter GLT1 have been demonstrated in rats with induced neuropathic pain. The dynamics of expression of high-affinity glutamate transporter subtypes and pattern of nociceptive pointed at complex relations between the functional state of glutamate transport system and the levels of analgesia provided by the tested compounds. The glutamate transport system has been also studied in co-cultures of dorsal root ganglion (DRG) neurons and spinal glial cells. In this in vitro model system, that partially recapitulates primary pain signaling path, both glial and neuronal glutamate carrier proteins undergo changes in expression, as well as post-translational modifications, including proteolytic truncation. Such regulated cleavage depends on phosphorylation state of intracellular domains of glutamate carrier proteins. These functional modifications alter cell surface targeting of glutamate transporters, as well as elicit downstream signaling. This also affects GluT interaction with other components of the glutamate sensing- and metabolizing machinery, including mechanisms of refilling and recycling of synaptic vesicles in DRG neurons and spinal glia. The elucidated regulatory pathways seem to provide fine tuning of excitatory signaling in the spinal cord and, can, thus, emerge as prospective drug targets for chronic pain treatment. Our recent data indicate that one of the direct modes of transporter signaling is triggered by cell death-associated proteases, caspases. Low sublethal doses of some of pro-apoptosis agents (e.g. Alzheimer’s beta-amyloid, glutamate receptor ligands, cytokines) activate caspases, that cleave glutamate transporters GLAST, GLT1, EAAC1 and EAAT4 at their cytoplasmic C- or N-terminal domains.. Such an unusual signaling via glutamate transporters is mediated both by functionally modified, truncated C-terminal domains and by bioactive peptides that are produced by the caspase-dependent cleavage. These soluble peptides contain several short conserved motifs that functionally interact with other cytoplasmic, mitochondrial or nuclear signaling complexes. The truncation of EAAC1 produces peptides that contain PDZ domain-binding motif, as well as a stretch of 8 aa residues present in 82-FIP, a novel RNA- binding protein that also interacts with FMRP, fragile X mental retardation protein. Soluble C-terminal fragments of EAAT4 could also interfere with protein translation machinery via phosphorylation of PHAS1. In case of GLAST, the C-terminus is a component of a cytoplasmic scaffolding complex interacting with FXYD2/γ subunit of Na+, K+ ATPase. Glutamate-induced activation of GLAST recruits to the cell surface more transporter molecules that are complexed with FXYD2/ γ subunit and, thus, activates the astroglial sodium pump, presumably due to the modulatory effect of γ subunit on the kinetic parameters of the catalytic α-subunit of Na+,K+ ATPase. Thus, neurotransmitter transporters, that represent novel targets for caspases, can act as scaffolding / shuttle proteins and are capable of exhibiting receptor-like, signal-transducing properties, that could possibly affect neuronal function in some neurological and cognitive disorders, such as brain ischemia, ALS, or Alzheimer’s disease.

A fixed-dose combination (FDC) is a drug product in which two or more separate drug components (active pharmaceutical ingredients) are combined in a single-dosage form. Interest in developing FDCs is increasing in a range of diseases. This project investigated the regulatory environment for FDCs in the EU and US. A review of the FDC guidelines set forth by the EMA, FDA, and ICH, followed by interviews of key informants in industry, identified 5 main industry concerns related to development of FDCs. These concerns were presented to key informants from both the EU and US regulatory authorities. It was clear from the results that the current regulatory environment for FDCs lacks consistency. This may create a barrier to innovation moving from the laboratory to the clinic, as companies cannot clearly see the development path requirements. This project also highlighted certain challenges that currently face the regulatory world: how to improve the role of regulatory science and provide clear quantification in assessment decisions; the role of guidelines and their impact on innovation; and, most important, the question of globalization and how to move toward a more harmonized regulatory system.

Tetrahydrobiopterin (BH4) is implicated in the development and maintenance of chronic pain. After injury/inflammation, the biosynthesis of BH4 is markedly increased in sensory neurons, and the pharmacological and genetic inhibition of BH4 shows analgesic effects in pre-clinical animal pain models. Intrathecal injections of BH4 have been shown to induce and enhance pain-like behaviours in rats, suggesting that under chronic pain conditions BH4 may act by facilitating central sensitisation. So far it is unknown whether BH4 acts on peripheral sites of the somatosensory system or whether BH4 per se provokes nociceptive pain behaviours. The purpose of this study was therefore to investigate the acute nociceptive effects of intraplantar injection of BH4. BH4 was found to induce dose-dependent licking/biting of the paw lasting 5 min, which was not observed following an injection of biopterin (inactive BH4 metabolite). Paw swelling, measured as paw thickness and weight, was not observed after BH4 injection. To explore possible mechanisms of action of BH4, the effect of local pre-treatment with indomethacin, Nω-nitro-l-arginine methyl ester, Nω-nitro-l-arginine, capsazepine and ruthenium red was tested. Morphine served as a positive control. Intraplantar pre-injection of morphine dose-dependently inhibited BH4-induced nociception, while none of the other compounds showed any statistical significant antinociception. These results suggest that BH4 exhibits nociceptive properties at peripheral sites of the somatosensory system, proposing an as yet unexplored involvement of BH4 in peripheral nociceptive processes. However, this appears not to be mediated through nitric oxide and prostaglandin release or by activation of the transient receptor potential vanilloid 1.

Background Apparent issues with the treatment and management of complex, chronic, and multifactorial diseases with monotherapies are becoming more prevalent, with a potential solution being fixed-dose combinations (FDCs). There is a certain stigma associated with FDCs, namely after the bans in the mid- to late 20th century; however, FDCs have proven useful in improving efficacy, reducing adverse effects, prolonging marketability, and producing new therapeutic entities. In addition to this, FDCs may be advantageous in increasing patient compliance and reducing off-label use. Methods FDCs authorized by the European Union in the past 5 years were analyzed according to benefit-risk and clinical trial design. Results An overall stable authorization of FDCs from 2009 to 2014 was observed, with most being developed to treat cardiac- and immune-related disorders. The aforementioned bans have led to stricter guidelines and regulations on FDCs; however, the examples presented demonstrate that the clinical guidelines from the European Medicines Agency are flexible within limits and may be altered given proper justification. Conclusion With off-label use, profitability, and reimbursement threatening the development of FDCs, it is the patients who end up suffering the most. The industry, regulatory bodies, and patients need to unite for the successful development of new FDCs.

Neurons responsible for sensing noxious stimuli and conducting pain signals from periphery to the spinal cord are predominantly glutamatergic. Members of the SLC1A family of high-affinity glutamate transporters (GluTs) are differentially expressed in sensory neurons and surrounding glial cells. These plasma membrane proteins along with glutamate/cystine exchanger, light chain of cystine/glutamate exchanger, are responsible for fine tuning of extracellular glutamate concentrations and, thus, for modulation of excitatory signalling in the spinal cord. Emerging data point at key roles of GluTs in molecular mechanisms of chronic pain and analgesia, incl. development of opioid tolerance. Pharmacological inhibition or antisense down-regulation of spinal GluTs can induce/aggravate pain behaviours, whereas increasing of expression of GluTs by viral gene transfer or positive pharmacological modulators can mitigate chronic pain. Furthermore, some drugs, originally introduced for targeting different pathological conditions, but in parallel exhibiting analgesic properties (e.g. anti-convulsants valproate and riluzole, β-lactam- and tetracycline antibiotics, tricyclic anti-depressants), can enhance glutamate transport in the spinal cord. Thus, molecular modulation of GluTs may turn into prospective therapeutic approach for the management of chronic pain. However, precise pharmacological targeting of this transport system requires in-depth elucidation of molecular factors and signalling pathways underlying expression and activity of individual GluT subtypes, including their splice variants. Neurons conducting pain signals from periphery to the spinal cord are predominantly glutamatergic. High-affinity glutamate transporters (GluTs) regulate extracellular glutamate concentrations and, thus, modulate excitatory signalling in pain circuits. The present review critically analyses accumulated data on the roles of GluTs in molecular mechanisms of chronic pain, as well as perspectives for targeting this transport system in pain therapies.

The use of fixed-dose combinations (FDCs) in the daily practice of pharmacotherapy is increasing after years in the shadows. The main reasons for this renewed popularity are the increasing number of drugs prescribed per patient and the complexity of current pharmacotherapy. A lack of efficacy of current monotherapies in many diseases together with advances in knowledge on pathophysiological disease mechanisms have also created a push towards development of new FDCs. For the regulatory authorities in Europe, however, it is unclear whether FDCs in general have a positive benefit–risk balance. Hence, more research is needed to show that use of FDCs improves treatment effectiveness through better compliance, adherence and quality of life for patients, which may lead to a positive pharmacoeconomical benefit for society. Evidence-based data are thus needed, especially for those patient groups requiring multiple drugs—for example, the elderly. In this context, hospital practice regarding FDCs is crucial, as the recommended pharmacotherapy at discharge of the patient serves as a role model for outpatient care, and therefore needs greater recognition. The benefit–risk balance and pharmacoeconomical consequences of FDCs should also be a subject for attention in the hospital pharmacy setting.