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Pharmaceutics Mar 2021Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in... (Review)
Review
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
PubMed: 33810493
DOI: 10.3390/pharmaceutics13040450 -
Pharmaceuticals (Basel, Switzerland) Mar 2021Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus,...
Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, mRNA, and mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.
PubMed: 33809508
DOI: 10.3390/ph14030267 -
Brain Sciences Mar 2021Reducing the progress of neurodegeneration is a key goal in Huntington´s disease (HD). A previously performed systematic screening for medications with neuroprotective...
Reducing the progress of neurodegeneration is a key goal in Huntington´s disease (HD). A previously performed systematic screening for medications with neuroprotective features identified tricyclic antidepressants and neuroleptics as neuroprotective and mitochondrioprotective agents. Here, we analyzed the characteristics of disease manifestation, progression and potential beneficial effects in HD patients treated with afore-mentioned medications compared to un- and otherwise treated motor-manifest patients in a large real-world cohort over two years. We analyzed cross-sectional data of the largest cohort worldwide of motor-manifest HD patients using the ENROLL-HD database, including demographic, moleculargenetic, clinical-motoric, cognitive and functional data. Longitudinal data of up to two years were obtained to analyze potential effects on disease progression between groups with different medications used. Data were analyzed using repeated ANOVA-analyses while controlling for the co-variates age and CAG-repeat length. We identified = 7397 motor-manifest HD patients using no or different medication (HD-ctrl) and subgroups treated with clomipramine ( = 56), clozapine ( = 66), chlorpromazine ( = 17), doxepine ( = 34) and desi-, imi- or trimipramine ( = 19). Demographic parameters, disease onset and CAP-score did not differ. Total motor scores (TMS) at baseline were higher in patients treated with clozapine ( < 0.001), chlorpromazine and clomipramine ( < 0.05) compared to HD-ctrl with higher sub scores for bradykinesia (all < 0.01) and dystonia in clozapine treated patients ( < 0.001). Functional and cognitive capacities were worse in medication groups in comparison to HD-ctrl at baseline ( < 0.001). Repeated measures analysis of variance documented no differences regarding motoric, functional and cognitive disease progressions between groups. We identified group differences, potentially caused by side effects or potential selection bias in terms of bradykinetic motoric symptoms, more dystonia and lower functional and cognitive performance in some treatment groups at baseline, which were not entirely explained because of underlying fundamental characteristics. Disease progression regarding clinical, functional and cognitive outcomes over two years was not affected by any of the treatment groups compared to HD-ctrl. Our data do not support our hypothesis of a potential neuroprotective effect of these drugs on disease progression.
PubMed: 33805940
DOI: 10.3390/brainsci11040413 -
Neurological Research and Practice Mar 2021Insomnia is defined as difficulties of initiating and maintaining sleep, early awakening and poor subjective sleep quality despite adequate opportunity and circumstances...
Insomnia is defined as difficulties of initiating and maintaining sleep, early awakening and poor subjective sleep quality despite adequate opportunity and circumstances for sleep with impairment of daytime performance. These components of insomnia - namely persistent sleep difficulties despite of adequate sleep opportunity resulting in daytime dysfunction - appear secondary or co-morbid to neurological diseases. Comorbid insomnia originates from neurodegenerative, inflammatory, traumatic or ischemic changes in sleep regulating brainstem and hypothalamic nuclei with consecutive changes of neurotransmitters. Symptoms of neurological disorders (i.e motor deficits), co-morbidities (i.e. pain, depression, anxiety) and some disease-specific pharmaceuticals may cause insomnia and/or other sleep problems.This guideline focuses on insomnias in headaches, neurodegenerative movement disorders, multiple sclerosis, traumatic brain injury, epilepsies, stroke, neuromuscular disease and dementia.The most important new recommendations are: Cognitive behavioral therapy (CBTi) is recommended to treat acute and chronic insomnia in headache patients. Insomnia is one of the most frequent sleep complaints in neurodegenerative movement disorders. Patients may benefit from CBTi, antidepressants (trazodone, doxepin), melatonin and gaba-agonists. Insomnia is a frequent precursor of MS symptoms by up to 10 years. CBTi is recommended in patients with MS, traumatic brain injury and. Melatonin may improve insomnia symptoms in children with epilepsies. Patients with insomnia after stroke can be treated with benzodiazepine receptor agonists and sedating antidepressants. For patients with dementia suffering from insomnia trazodone, light therapy and physical exercise are recommended.
PubMed: 33691803
DOI: 10.1186/s42466-021-00106-3 -
Toxicology Letters Jun 2021The present study aimed at incorporating active renal excretion via the organic cation transporter 2 (OCT2) into a generic rat physiologically based kinetic (PBK) model...
The present study aimed at incorporating active renal excretion via the organic cation transporter 2 (OCT2) into a generic rat physiologically based kinetic (PBK) model using an in vitro human renal proximal tubular epithelial cell line (SA7K) and mepiquat chloride (MQ) as the model compound. The Vmax (10.5 pmol/min/mg protein) and Km (20.6 μM) of OCT2 transport of MQ were determined by concentration-dependent uptake in SA7K cells using doxepin as inhibitor. PBK model predictions incorporating these values in the PBK model were 6.7-8.4-fold different from the reported in vivo data on the blood concentration of MQ in rat. Applying an overall scaling factor that also corrects for potential differences in OCT2 activity in the SA7K cells and in vivo kidney cortex and species differences resulted in adequate predictions for in vivo kinetics of MQ in rat (2.3-3.2-fold). The results indicate that using SA7K cells to define PBK parameters for active renal OCT2 mediated excretion with adequate scaling enables incorporation of renal excretion via the OCT2 transporter in PBK modelling to predict in vivo kinetics of mepiquat in rat. This study demonstrates a proof-of-principle on how to include active renal excretion into generic PBK models.
Topics: Animals; Cell Line; Epithelial Cells; Humans; Kidney; Kidney Tubules, Proximal; Models, Biological; Organic Cation Transporter 2; Piperidines; Plant Growth Regulators; Rats
PubMed: 33639197
DOI: 10.1016/j.toxlet.2021.02.013 -
Journal of Traditional Chinese Medicine... Feb 2021To evaluate the clinical efficacy and safety of combined acupuncture and Western Medicine in the treatment of post-stroke depression using a meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the clinical efficacy and safety of combined acupuncture and Western Medicine in the treatment of post-stroke depression using a meta-analysis.
METHODS
The China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, Chinese Biomedical Literature Database, PubMed, Embase, and the Cochrane Library were searched from their establishment to August 2018 for randomized controlled trials (RCTs) of combined acupuncture and Western Medicine to treat post-stroke depression. Two researchers independently extracted and cross-checked data, and then applied the modified Jadad scale and the Cochrane-recommended assessment method to evaluate the risk of bias. Review Manager 5.3 was used to conduct the meta-analysis.
RESULTS
A total of 1860 patients in 24 RCTs were analyzed. The results of the Meta-analysis showed that: (a) The effective rate of acupuncture + fluoxetine hydrochloride vs fluoxetine hydrochloride was significant [relative risk (RR) = 1.16, 95% confidence interval (CI) (1.08, 1.26)], as was that of acupuncture + flupentixol/melitracen vs flupentixol/melitracen [RR = 1.23, 95% CI (1.10, 1.37)]. (b) When analyzing Hamilton Depression Scale (HAMD)-17 scores, six trials showed that acupuncture combined with Western Medicine was superior to Western Medicine alone, and could relieve the depressive symptoms of patients. For HAMD-24 scores, five trials were included for acupuncture + fluoxetine hydrochloride vs fluoxetine hydrochloride, with significance at 2 weeks [WMD = -6.51, 95% CI(- 8.62, - 4.40)], as well as at 4 weeks [WMD = -8.40, 95% CI (-11.86, -4.94)] and 8 weeks. (c)For the activities of daily living scale, acupuncture + fluoxetine hydrochloride vs fluoxetine hydrochloride [WMD = 22.65, 95% CI (18.34, 26.95)], acupuncture + flupentixol/melitracen vs flupentixol/melitracen [WMD = 8.08, 95% CI (2.57, 13.59)], acupuncture + sertraline hydrochloride vs sertraline hydrochloride [WMD = 6.94, 95% CI (3.59, 10.29)], and acupuncture + doxepin hydrochloride vs doxepin hydrochloride [WMD = 18.80, 95% CI (15.84, 21.76)] had significance. (d) For Treatment Emergent Symptom Scale scores, there was significance in all four included studies.
CONCLUSION
The therapeutic effects of acupuncture combined with Western Medicine on post-stroke depression are often better than those of Western Medicine alone, and fewer adverse reactions occur. However, more high-quality RCTs are needed to further confirm these findings.
Topics: Activities of Daily Living; Acupuncture Therapy; Antidepressive Agents; Combined Modality Therapy; Depression; Fluoxetine; Humans; Randomized Controlled Trials as Topic; Stroke; Treatment Outcome
PubMed: 33522192
DOI: 10.19852/j.cnki.jtcm.2021.01.002 -
JAAD Case Reports Feb 2021
PubMed: 33521215
DOI: 10.1016/j.jdcr.2020.12.017 -
European Journal of Pharmacology Apr 2021The spread of the corona virus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been intensifying in the past...
The spread of the corona virus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been intensifying in the past year, posing a huge threat to global health. There is an urgent need for effective drugs and vaccines to fight the COVID-19, but their advent may not be quite fast. Drug repurposing is a feasible strategy in the current situation, which could greatly shorten drug development time and help to response quickly to the novel virus outbreak. It has been reported that histamine H receptor antagonists have broad-spectrum antiviral effects. Therefore, in this study, we aim to screen potential drugs among histamine H receptor antagonists that may inhibit SARS-CoV-2 infection. Based on the model of angiotensin-converting enzyme 2 (ACE2) overexpressing HEK293T cell membrane chromatography (CMC), five FDA-approved histamine H receptor antagonists were found to have bioaffinity to ACE2. Then we determined the interaction between these drugs and ACE2 by frontal analysis and surface plasmon resonance (SPR), which consistently demonstrated that these hits bind to ACE2 at micromolar levels of affinity. Through the pseudovirus assay, we finally identified that doxepin could inhibit SARS-CoV-2 spike pseudovirus from entering the ACE2-expressing cell, reducing the infection rate to 25.82%. These preliminary results indicate that the histamine H receptor antagonist, doxepin, is a viable drug candidate for clinical trials. Therefore, we hope the work timely provides rational help for developing anti-SARS-CoV-2 drugs to control the rapid spread of SARS-CoV-2.
Topics: Angiotensin-Converting Enzyme 2; Antiviral Agents; COVID-19; Doxepin; Drug Repositioning; HEK293 Cells; Histamine H1 Antagonists; Humans; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33497607
DOI: 10.1016/j.ejphar.2021.173897 -
Cureus Sep 2020Background and objectives Sleep medicine has been one of the fastest-growing medical fields in recent years. The industry plays a big role in developing new...
Background and objectives Sleep medicine has been one of the fastest-growing medical fields in recent years. The industry plays a big role in developing new medications and devices for both diagnosis and treatment of sleep-related problems. We analyzed payments made by industry to physicians from 2014 through 2018 based on the Open Payments Program data. Methods Centers for Medicare and Medicaid Services Open Payment Program and American Board of Psychiatry and Neurology databases were explored to elicit financial relationships between industry and sleep neurologists. Results Payments made by industry to sleep neurologists have been steadily increasing from 2014 through 2018. Approximately 16% to 22% of sleep certified neurologists received payments from industry during the study period. Interestingly, the payments made to the top 10% of the sleep physicians contributed approximately 85% to 96% of the total payments. The top two categories to which the highest payments were made were compensation for services and royalty and/or licensing fees. Silenor® (doxepin), Xyrem® (sodium oxybate), Aptiom® (eslicarbazepine acetate), Belsomra® (suvorexant), and Fycompa® (perampanel) were most of the drugs, which made the highest payments, that got approved by the Food and Drug Administration in the last decade. Conclusions It seems that the industry is spending significant amounts of money in educating the physicians and in marketing the newer drugs. This analysis of the data on payments from industry is very useful in identifying any potential conflicts of interest from physicians. Further analyses are needed to study the trends of physician practice behavior and decision making.
PubMed: 33110732
DOI: 10.7759/cureus.10597 -
Pharmaceuticals (Basel, Switzerland) Sep 2020Depression is a global threat. Tricyclic antidepressants (TCAs) are still efficacious in treating depression, albeit with more side effects. Cyclodextrins (CDs) with a...
Supramolecular Complexes of β-Cyclodextrin with Clomipramine and Doxepin: Effect of the Ring Substituent and Component of Drugs on Their Inclusion Topologies and Structural Flexibilities.
Depression is a global threat. Tricyclic antidepressants (TCAs) are still efficacious in treating depression, albeit with more side effects. Cyclodextrins (CDs) with a suitable nanocavity are potential drug carriers and can enhance the drug bioavailability. Aiming for an atomistic understanding of the CD encapsulation facilitating the improvement of drug stability and the reduction of side effects, a comprehensive study series of the β-CD-TCA inclusion complexes through single crystal X-ray diffraction and density functional theory (DFT) calculation was undertaken. This work reports the supramolecular complexes of β-CD with two pivotal TCAs, clomipramine (CPM; ) and doxepin (DXP; ). The different inclusion topologies of the β-CD-TCA complexes were notable. X-ray analysis revealed that, in the CPM B-ring (without chloro group) was entrapped in the β-CD cavity, whereas, in the -DXP A-ring and the -DXP B-ring were disordered in the cavity, yielding energetically favorable complexes primarily maintained by intermolecular C-Hπ interactions, as indicated by DFT calculation. Because both wings of TCAs were similar, an alternative inclusion scenario of the A-ring was evidenced crystallographically in four other TCA complexes. The enhanced TCA thermodynamic stabilities via CD inclusion complexation helped to reduce the side effects and to increase the bioavailability. Moreover, the scrutinization of six TCAs in different lattice circumstances revealed the greater TCA structural flexibilities for their optimum pharmacological activity while binding with proteins.
PubMed: 33003431
DOI: 10.3390/ph13100278