Herb-drug interactions: A short review on central and peripheral nervous system drugs.

Herbal medicines are widely perceived as natural and safe remedies. However, their concomitant use with prescribed drugs is a common practice, often undertaken without full awareness of the potential risks and frequently without medical supervision. This practice introduces a tangible risk of herb-drug interactions, which can manifest as a spectrum of consequences, ranging from acute, self-limited reactions to unpredictable and potentially lethal scenarios. This review offers a comprehensive overview of herb-drug interactions, with a specific focus on medications targeting the Central and Peripheral Nervous Systems. Our work draws upon a broad range of evidence, encompassing preclinical data, animal studies, and clinical case reports. We delve into the intricate pharmacodynamics and pharmacokinetics underpinning each interaction, elucidating the mechanisms through which these interactions occur. One pressing issue that emerges from this analysis is the need for updated guidelines and sustained pharmacovigilance efforts. The topic of herb-drug interactions often escapes the attention of both consumers and healthcare professionals. To ensure patient safety and informed decision-making, it is imperative that we address this knowledge gap and establish a framework for continued monitoring and education. In conclusion, the use of herbal remedies alongside conventional medications is a practice replete with potential hazards. This review not only underscores the real and significant risks associated with herb-drug interactions but also underscores the necessity for greater awareness, research, and vigilant oversight in this often-overlooked domain of healthcare.

Remyelination in humans due to a retinoid-X receptor agonist is age-dependent.

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan.

The time to develop treatments for diabetic neuropathy.

BACKGROUND: Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN). METHODS: We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. RESULTS: Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. EXPERT OPINION: The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.

Botulinum Toxin and Neuronal Regeneration after Traumatic Injury of Central and Peripheral Nervous System.

Botulinum neurotoxins (BoNTs) are toxins produced by the bacteria Clostridiumbotulinum, the causing agent for botulism, in different serotypes, seven of which (A-G) are well characterized, while others, such as H or FA, are still debated. BoNTs exert their action by blocking SNARE (soluble N-ethylmale-imide-sensitive factor-attachment protein receptors) complex formation and vesicle release from the neuronal terminal through the specific cleavage of SNARE proteins. The action of BoNTs at the neuromuscular junction has been extensively investigated and knowledge gained in this field has set the foundation for the use of these toxins in a variety of human pathologies characterized by excessive muscle contractions. In parallel, BoNTs became a cosmetic drug due to its power to ward off facial wrinkles following the activity of the mimic muscles. Successively, BoNTs became therapeutic agents that have proven to be successful in the treatment of different neurological disorders, with new indications emerging or being approved each year. In particular, BoNT/A became the treatment of excellence not only for muscle hyperactivity conditions, such as dystonia and spasticity, but also to reduce pain in a series of painful states, such as neuropathic pain, lumbar and myofascial pain, and to treat various dysfunctions of the urinary bladder. This review summarizes recent experimental findings on the potential efficacy of BoNTs in favoring nerve regeneration after traumatic injury in the peripheral nervous system, such as the injury of peripheral nerves, like sciatic nerve, and in the central nervous system, such as spinal cord injury.

Calcitonin gene-related peptide antagonists versus botulinum toxin A for the preventive treatment of chronic migraine protocol of a systematic review and network meta-analysis: A protocol for systematic review.

BACKGROUND: Although calcitonin gene-related peptide antagonists and botulinum toxin A have been shown efficacy in preventing chronic migraine, there is no direct evidence for their comparative effectiveness. This review is to assess the comparative effectiveness and safety of calcitonin gene-related peptide antagonists and botulinum toxin A for chronic migraine using network meta-analysis. METHODS: OVID MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials will be searched for relevant randomized controlled trials from their inception to December 2019 without language restriction. We will include trials testing the effectiveness of calcitonin gene-related peptide antagonists or botulinum toxin A in patients with chronic migraine. The outcomes are mean change from baseline in the number of headache days, the mean change from baseline in the number of migraine days, the mean change from baseline in headache hours, responder rate, and adverse events rate. The methodological quality of the included randomized controlled trials will be evaluated using Cochrane Collaboration's risk of bias tool. Standardized mean difference will be used to synthesize continuous variables and risk ratio will be used to synthesize categorical variables. Pairwise and network meta-analysis will be performed using a frequentist method in netmeta package (R 3.5.0, www.r-project.org). RESULTS: Ethical approval and informed consent are not required for this systematic review. The results will be submitted to a peer-reviewed journal and conference abstracts for publication. CONCLUSION: The result of the review will systematically provide suggestions for clinicians, patients, and policy makers in the treatment of chronic migraine.PROSPERO registration number: CRD42018089201.

Food-induced stimulation of the antisecretory factor to improve symptoms in Meniere's disease: our results.

PURPOSE: Specially processed cereals (SPC) that increase endogenous antisecretory factor (AF) synthesis have been proposed to improve symptoms of Meniere's disease (MD) with controversial results. The aim of this study was to evaluate the effects of SPC in patients with definite unilateral MD and compare the results to a treatment protocol with intravenous glycerol and dexamethasone. METHODS: Thirteen patients with unilateral MD were treated with SPC and 13 patients were treated with intravenous glycerol and dexamethasone for 12 months. Audio-vestibular evaluation was performed before (T0) and at the end of the treatments (T12). The number of vertigo spells were evaluated before and after therapy and the Efficacy Index (EI) was calculated. Questionnaires for hearing loss (HHIA), tinnitus (THI) and quality of life (TFL) were administered. RESULTS: EI decreased in the SPC group in the second semester compared to the first although not significantly (p = 0.6323). There was a significant reduction for THI score in the SPC group at T12 (p = 0.0325). No significant differences were found between the two groups at T0 (p = 0.4723), while a significant difference was found at T12 (p = 0.0041). Quality of life showed an improvement in daily activities in the SPC group compared to infusion therapy group. CONCLUSION: Our study shows a reduced number of vertigo attacks and a positive effect on the discomfort generated by tinnitus and quality of life in patients with unilateral MD treated with SPC and when compared to patients treated with intravenous glycerol and dexamethasone. No effects on hearing thresholds were noted in both groups.

Modeling drug exposure in rodents using e-cigarettes and other electronic nicotine delivery systems.

Smoking tobacco products is the leading cause of preventable death worldwide. Coordinated efforts have successfully reduced tobacco cigarette smoking in the United States; however, electronic cigarettes (e-cigarette) and other electronic nicotine delivery systems (ENDS) recently have replaced traditional cigarettes for many users. While the clinical risks associated with long-term ENDS use remain unclear, advancements in preclinical rodent models will enhance our understanding of their overall health effects. This review examines the peripheral and central effects of ENDS-mediated exposure to nicotine and other drugs of abuse in rodents and evaluates current techniques for implementing ENDS in preclinical research.

Out-of-pocket costs are on the rise for commonly prescribed neurologic medications.

OBJECTIVE: To determine out-of-pocket costs for neurologic medications in 5 common neurologic diseases. METHODS: Utilizing a large, privately insured, health care claims database from 2004 to 2016, we captured out-of-pocket medication costs for patients seen by outpatient neurologists with multiple sclerosis (MS), peripheral neuropathy, epilepsy, dementia, and Parkinson disease (PD). We compared out-of-pocket costs for those in high-deductible health plans compared to traditional plans and explored cumulative out-of-pocket costs over the first 2 years after diagnosis across conditions with high- (MS) and low/medium-cost (epilepsy) medications. RESULTS: The population consisted of 105,355 patients with MS, 314,530 with peripheral neuropathy, 281,073 with epilepsy, 120,720 with dementia, and 90,801 with PD. MS medications had the fastest rise in monthly out-of-pocket expenses (mean [SD] $15 [$23] in 2004, $309 [$593] in 2016) with minimal differences between medications. Out-of-pocket costs for brand name medications in the other conditions also rose considerably. Patients in high-deductible health plans incurred approximately twice the monthly out-of-pocket expense as compared to those not in these plans ($661 [$964] vs $246 [$472] in MS, $40 [$94] vs $18 [$46] in epilepsy in 2016). Cumulative 2-year out-of-pocket costs rose almost linearly over time in MS ($2,238 [$3,342]) and epilepsy ($230 [$443]). CONCLUSIONS: Out-of-pocket costs for neurologic medications have increased considerably over the last 12 years, particularly for those in high-deductible health plans. Out-of-pocket costs vary widely both across and within conditions. To minimize patient financial burden, neurologists require access to precise cost information when making treatment decisions.

Therapeutic strategies that act on the peripheral nervous system in primary headache disorders.

Introduction: Acute and preventive treatment of primary headache disorders is not completely resolved with regard to efficacy, safety, and tolerability. Hence, peripheral and central neuromodulation can provide therapeutic alternatives in drug-resistant cases. Peripheral targets of neuromodulation include invasive and non-invasive neurostimulation and electrical and chemical nerve and ganglion blockades. Areas covered: A PubMed search of papers published from January 2012 to October 2018 was conducted. The goal of this review was to analyze the efficacy and safety of invasive (implantable) peripheral neurostimulation methods (the occipital nerve, the cervical branch of vagal nerve, the sphenopalatine ganglion) and non-invasive (transcutaneous) peripheral neurostimulation methods (the occipital nerve, the supraorbital nerve, and the cervical and auricular branches of the vagal nerve), based on the results of published clinical trials and case series. Acting also on the peripheral nervous system, peripheral nerve (i.e. greater occipital nerve) and ganglion (i.e. sphenopalatine ganglion) blockades, botulinum neurotoxin type A-hemagglutinin complex therapies, and calcitonin gene-related peptide-related monoclonal antibody treatments in this patient population are also discussed. Expert opinion: This review summarizes the latest results on the therapeutic strategies acting on the periphery in primary headache disorders. These therapeutic options are minimally invasive or non-invasive, efficacious, safe, and well tolerated.

Using a new high-throughput video-tracking platform to assess behavioural changes in Daphnia magna exposed to neuro-active drugs.

Recent advances in imaging allow to monitor in real time the behaviour of individuals under a given stress. Light is a common stressor that alters the behaviour of fish larvae and many aquatic invertebrate species. The water flea Daphnia magna exhibits a vertical negative phototaxis, swimming against light trying to avoid fish predation. The aim of this study was to develop a high-throughput image analysis system to study changes in the vertical negative phototaxis of D. magna first reproductive adult females exposed to 0.1 and 1 µg/L of four neuro-active drugs: diazepam, fluoxetine, propranolol and carbamazepine. Experiments were conducted using a custom designed experimental chamber containing four independent arenas and infrared illumination. The apical-located visible light and the GigE camera located in front of the arenas were controlled by the Ethovision XT 11.5 sofware (Noldus Information Technology, Leesburg, VA). Total distance moved, time spent per zone (bottom vs upper zones) and distance among individuals were analyzed in dark and light conditions, and the effect of different intensities of the apical-located visible light was also investigated. Results indicated that light intensity increased the locomotor activity and low light intensities allowed to better discriminate individual responses to the studied drugs. The four tested drugs decreased the response of exposed organisms to light: individuals moved less, were closer to the bottom and at low light intensities were closer each other. At high light intensities, however, exposed individuals were less aggregated. Propranolol, carbamazepine and fluoxetine induced the most severe behavioural effects. The tested drugs at environmental relevant concentrations altered locomotor activity, geotaxis, phototaxis and aggregation in D. magna individuals in the lab. Therefore the new image analysis system presented here was proven to be sensitive and versatile enough to detect changes in diel vertical migration across light intensities and low concentration levels of neuro-active drugs.

Peripheral nervous system effects in the PS19 tau transgenic mouse model of tauopathy.

It is well known that transgenic mice overexpressing human tau protein with P301S mutation driven by the mouse prion protein promoter show clasping and limb retraction, hunched back and paralysis, followed by inability to feed that results in death around 12 months of age. To understand these motor deficits, we have carried out rotarod tests on PS19 line and demonstrated how they worsened during aging. Then, we have analyzed if these phenotypic characteristics correlate with sciatic nerve degeneration. We first demonstrated by western blot and immunohistochemistry that the sciatic nerve expresses the transgenic tau protein; then, electron microscopy studies showed alterations in myelin, mainly a detachment of myelin lamellae at Schmidt-Lanterman clefts. Similar motor deficits and myelin alterations have been previously reported in tau knockout and overexpressing transgenic mice; taking into account that PS19 model is widely used to study tauopathies, we suggest that analyzing the expression of transgenic tau protein and myelin abnormalities in the sciatic nerve should be considered when studying some features as motor performance or survival.

Polyneuropathy by statins: case report / Polineuropatía por estatinas: descripción

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The role of nonmuscle myosin II in polydrug memories and memory reconsolidation.

Using pharmacologic and genetic approaches targeting actin or the actin-driving molecular motor, nonmuscle myosin II (NMII), we previously discovered an immediate, retrieval-independent, and long-lasting disruption of methamphetamine- (METH-) and amphetamine-associated memories. A single intrabasolateral amygdala complex infusion or systemic administration of the NMII inhibitor Blebbistatin (Blebb) is sufficient to produce this disruption, which is selective, having no retrieval-independent effect on memories for fear, food reward, cocaine, or morphine. However, it was unclear if Blebb treatment would disrupt memories of other stimulants and amphetamine class drugs, such as nicotine (NIC) or mephedrone (MEPH; bath salts). Moreover, many individuals abuse multiple drugs, but it was unknown if Blebb could disrupt polydrug memories, or if the inclusion of another substance would render Blebb no longer able to disrupt METH-associated memories. Therefore, the present study had two primary goals: (1) to determine the ability of Blebb to disrupt NIC- or MEPH-associated memories, and (2) to determine the ability of METH to modify other unconditioned stimulus (US) associations' susceptibility to Blebb. To this end, using the conditional place preference model, mice were conditioned to NIC and MEPH alone or METH in combination with NIC, morphine, or foot shock. We report that, unlike METH, there was no retrieval-independent effect of Blebb on NIC- or MEPH-associated memories. However, similar to cocaine, reconsolidation of the memory for both drugs was disrupted. Further, when combined with METH administration, NIC- and morphine-, but not fear-, associated memories were rendered susceptible to disruption by Blebb. Given the high rate of polydrug use and the resurgence of METH use, these results have important implications for the treatment of substance use disorder.

The Expanding Therapeutic Utility of Botulinum Neurotoxins.

Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation and delivery, together with highly sensitive analytical tools, will be key for the success of next generation BoNT clinical products.

Influence of Cholecystokinin-8 on Compound Nerve Action Potentials from Ventral Gastric Vagus in Rats.

OBJECTIVE: Vagus Nerve Stimulation (VNS) has shown great promise as a potential therapy for a number of conditions, such as epilepsy, depression and for Neurometabolic Therapies, especially for treating obesity. The objective of this study was to characterize the left ventral subdiaphragmatic gastric trunk of vagus nerve (SubDiaGVN) and to analyze the influence of intravenous injection of gut hormone cholecystokinin octapeptide (CCK-8) on compound nerve action potential (CNAP) observed on the same branch, with the aim of understanding the impact of hormones on VNS and incorporating the methods and results into closed loop implant design. METHODS: The cervical region of the left vagus nerve (CerVN) of male Wistar rats was stimulated with electric current and the elicited CNAPs were recorded on the SubDiaGVN under four different conditions: Control (no injection), Saline, CCK1 (100[Formula: see text]pmol/kg) and CCK2 (1000[Formula: see text]pmol/kg) injections. RESULTS: We identified the presence of A[Formula: see text], B, C1, C2, C3 and C4 fibers with their respective velocity ranges. Intravenous administration of CCK in vivo results in selective, statistically significant reduction of CNAP components originating from A and B fibers, but with no discernible effect on the C fibers in [Formula: see text] animals. The affected CNAP components exhibit statistically significant ([Formula: see text] and [Formula: see text]) higher normalized stimulation thresholds. CONCLUSION: This approach of characterizing the vagus nerve can be used in closed loop systems to determine when to initiate VNS and also to tune the stimulation dose, which is patient-specific and changes over time.

Efecto de la edad y el género sobre las consecuencias clínicas y económicas del tratamiento con especialidad farmacéutica de marca o genérica en pacientes con dolor neuropático periférico en práctica clínica habitual / Clinical and economic consequences of treating patients with peripheral neuropathic pain with brand name or generic drugs in routine clinical practice: The effects of age and sex

OBJETIVO: Analizar el efecto de la edad y el género sobre el dolor y los costes en pacientes con dolor neuropático periférico (DNp) crónico que inician tratamiento con gabapentina (marca) frente a gabapentina genérica (EFG). MÉTODOS: Estudio multicéntrico-retrospectivo, realizado con registros médicos electrónicos (RME) de pacientes de ambos géneros, > 18años, que iniciaron nuevo tratamiento con gabapentina de marca o genérico. Durante un año se midió la adherencia (ratio posesión medicación [RPM]) y la persistencia, la utilización de recursos sanitarios, los costes y la reducción del dolor. RESULTADOS: Se analizaron 1.369 RME (61,1% mujeres; edad 64,6 [15,9] años, 52,4% ≥ 65 años); marca: 400, EFG: 969. La persistencia y la adherencia fueron mayores con marca: 7,3 vs. 6,3 meses (p < 0,001) y 86,5 vs. 81,3% de RPM (p < 0,001). Con marca, se observaron costes sanitarios menores, tanto en < 65 como en ≥ 65años (diferencias medias por paciente de 221 Euros [IC95%: 59-382] y de 217 Euros [51-382], respectivamente [p < 0,01]), como en hombres (diferencias medias de 197 Euros [63-328]) o mujeres (diferencias de 239 Euros [96-397]), p = 0,005 y p = 0,004, respectivamente. Comparado con EFG, el tratamiento con marca mostró una reducción mayor del dolor: 13,5% (10,9-16,2) y 10,8% (8,2-13,5) en < 65 y ≥ 65 años, respectivamente (p < 0,001), así como del 10,7% (8,2-13,2) y del 13,8% (11,0-16,5) en mujeres y hombres, respectivamente (p < 0,001). CONCLUSIONES: Con independencia del género o la edad, los pacientes que iniciaron tratamiento del DNp con gabapentina de marca vs. genérico mostraron un mayor grado de adherencia y persistencia al tratamiento, repercutiendo en unos menores costes sanitarios, a la vez que se observaron mayores reducciones del dolor

OBJECTIVE: We aimed to analyse the effects of age and sex on pain and cost for patients with chronic peripheral neuropathic pain (PNP) who have started treatment with brand name gabapentin versus generic gabapentin (EFG). METHODS: We conducted a retrospective multicentre study using electronic medical records (EMR) for patients of both sexes, older than 18, who began treatment with brand name or generic gabapentin. Adherence (medication possession ratio [MPR]), persistence, use of healthcare resources, cost, and pain reduction were measured for one year. RESULTS: We analysed 1369 EMRs [61.1% women; mean age 64.6 (15.9), 52.4% ≥ 65 years]; 400 used brand name drugs while 969 used generic gabapentin. Persistence and adherence were higher in patients using brand name gabapentin (7.3 vs 6.3 months, P < .001; 86.5% vs 81.3% MPR, P < .001). Lower healthcare costs were observed in patients using brand-name gabapentin in both age groups (< 65 and ≥ 65). Mean difference in cost per patient amounted to Euros221 (95%CI: 59-382) and Euros 217 (95%CI: 51-382) in the < 65 and ≥ 65 age groups, respectively (P < .01). Mean difference in cost among men amounted to Euros 197 (63-328), while mean difference in cost among women amounted to Euros 239 (96-397) (P = .005 and P = .004, respectively). Compared with EFG, brand treatment showed greater pain relief: 13.5% (10.9-16.2) and 10.8% (8.2-13.5) in < 65 and ≥ 65year patients, respectively (P < .001), and 10.7% (8.2-13.2) and 13.8% (11.0-16.5) in women and men respectively (P < .001). CONCLUSIONS: Regardless of sex and age, patients who started PNP treatment with brand name medication showed greater persistence and adherence to treatment than those taking generic drugs. Brand name treatment also involved lower healthcare costs, and greater pain relief

miR-221-3p Inhibits Schwann Cell Myelination.

Following peripheral nerve injury, Schwann Cells (SCs) undergo dedifferentiation, proliferation, migration, and remyelination. Recent works demonstrated the importance of the short non-coding RNA (miRNAs) in SC dedifferentiation and remyelination after nerve injury. Previously, we found some miRNAs like miR-9, miR-221, miR-222 and miR-182 could regulate the proliferation and migration of SCs. Therefore, it is imperative to ask whether these miRNAs could regulate the myelination of SCs. Here we demonstrated that miR-221-3p could inhibit the myelination of SCs when co-cultured with dorsal root ganglion cells in vitro. In addition, NGF1-A binding protein 1 (Nab1) which was essential for SCs myelination could be downregulated by miR-221-3p. Suppressing the expression of Nab1 could reverse the promotion of miR-221-3p antagomir on SC myelination. The effects of miR-221-3p on SC myelination might be used to improve peripheral nerve regeneration, thus offering a new approach to peripheral nerve repair.

Growth hormone promotes neurite growth of spiral ganglion neurons.

Intact spiral ganglion neurons are a specific requirement for hearing rehabilitation in deaf patients by cochlear implantation. Neurotrophic growth factors have been proposed as effective tools to protect and regenerate spiral ganglion neurons that are degenerated in the majority of patients suffering from hearing loss. Here, we show that growth hormone (GH), a pleiotropic growth factor whose neurotrophic role in the inner ear is still unclear, significantly increases neurite extension, as well as neuronal branching, in spiral ganglion cell cultures derived from early postnatal rats. Our data suggest that GH can act as a potent neurotrophic factor for inner ear neurons, which specifically promotes neurite growth. These effects might be elicited in a direct way or, alternatively, by induction of other growth factors that account for the observed neurotrophic effects. Thus, we conlude that GH might represent a novel candidate for the treatment of neurodegeneration in the hearing-impaired inner ear that has the potential to ultimately improve the performance and outcome of modern auditory implants.