Increasing interest has recently been attracted towards the identification of natural compounds including those with antidepressant properties. Curcumin has shown promising antidepressant effect, ...however, its molecular target(s) have not been well defined. Based on the interaction between the neurotrophins and endocannabinoid system as well as their contribution to the emotional reactivity and antidepressant action, here we show that 4-week treatment with curcumin, similar to the classical antidepressant amitriptyline, results in the sustained elevation of brain nerve growth factor (NGF) and endocannabinoids in dose-dependent and brain region-specific fashion. Pretreatment with cannabinoid CB sub(1) receptor neutral antagonist AM4113, but not the CB sub(2) antagonist SR144528, prevents the enhancement of brain NGF contents. AM4113 exerts no effect by itself. Our findings by presenting the CB sub(1) receptor-mediated endocannabinoid signaling and NGF as novel targets for curcumin, suggest that more attention should be focused on the therapeutic potential of herbal medicines including curcumin.
Which medication, if any, to use to prevent the headache of pediatric migraine has not been established.
We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per ...kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.
A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.
There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).
Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG), which is considered to be involved in the therapeutic action of antidepressants. However, the mechanism ...underlying it remains unclear. By using cultured adult rat DG-derived neural precursors (ADP), we have already shown that antidepressants have no direct effects on ADP. Therefore, antidepressants may increase the proliferation of neural precursors in adult DG via unknown indirect mechanism. We have also shown that amitriptyline (AMI), a tricyclic antidepressant, induces the expressions of GDNF, BDNF, FGF2 and VEGF, common neurogenic factors, in primary cultured astrocytes (PCA). These suggest that AMI-induced factors in astrocytes may increase the proliferation of neural precursors in adult DG. To test this hypothesis, we examined the effects of AMI-induced factors and conditioned medium (CM) from PCA treated with AMI on ADP proliferation. The effects of CM and factors on ADP proliferation were examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation, but AMI-treated CM increased it. The receptors of GDNF, BDNF and FGF2, but not VEGF, were expressed in ADP. FGF2 significantly increased ADP proliferation, but not BDNF and GDNF. In addition, both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition, FGF2 in brain is mainly derived from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes.
This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the effects of amitriptyline for ...fibromyalgia are now dealt with in a separate review.Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage). It is recommended as a first line treatment in many guidelines. Neuropathic pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.
To assess the analgesic efficacy of amitriptyline for relief of chronic neuropathic pain, and the adverse events associated with its use in clinical trials.
We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with two clinical trial registries, and the reference lists of retrieved papers, previous systematic reviews, and other reviews; we also used our own hand searched database for older studies.
We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in chronic neuropathic pain conditions.
We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks' duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.
We included 15 studies from the earlier review and two new studies (17 studies, 1342 participants) in seven neuropathic pain conditions. Eight cross-over studies with 302 participants had a median of 36 participants, and nine parallel group studies with 1040 participants had a median of 84 participants. Study quality was modest, though most studies were at high risk of bias due to small size.There was no first-tier or second-tier evidence for amitriptyline in treating any neuropathic pain condition. Only third-tier evidence was available. For only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo (very low quality evidence).More participants experienced at least one adverse event; 55% of participants taking amitriptyline and 36% taking placebo. The risk ratio (RR) was 1.5 (95% confidence interval (CI) 1.3 to 1.8) and the number needed to treat for an additional harmful outcome was 5.2 (3.6 to 9.1) (low quality evidence). Serious adverse events were rare. Adverse event and all-cause withdrawals were not different, but were rarely reported (very low quality evidence).
Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but only a minority of people will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.
•A novel polythiophene/graphene oxide (PTh/GO) nanostructured coating was introduced.•PTh/GO was prepared on inner surface of stainless steel tube by electrochemical method.•It was used for on-line ...electrochemically controlled in-tube solid phase microextraction.•Antidepressants drugs of amitriptyline and doxepin were extracted as model analytes.•The method was applied for analysis of the drugs in human urine and plasma samples.
In this work, a novel polythiophene/graphene oxide (PTh/GO) nanostructured coating was introduced for on-line electrochemically-controlled in-tube solid phase microextraction of amitriptyline (AMI) and doxepin (DOX) as antidepressant drugs. The PTh/GO coating was prepared on the inner surface of a stainless steel tube by a facile in-situ electro-deposition method and it was used as a working electrode for electrochemically control in-tube solid phase microextraction. In the PTh/GO coating, GO acts as an anion dopant and sorbent. The PTh/GO coating, compared to PTh and GO coatings, exhibited enhanced long lifetime, good mechanical stability and a large specific surface area. Regarding the in-tube SPME, some important factors such as the extraction and desorption voltage, extraction and desorption times and flow rates of the sample solution and eluent, which could affect the extraction and separation efficiency of the analytes, were optimized. Total analysis time of this method including the online extraction and desorption time was about 21min for each sample. AMI and DOX were extracted, separated and determined with limits of detection as small as 0.3μgL−1 and 0.5μgL−1, respectively. This method showed good linearity in the range of 0.7–200μgL−1, 2.3–200μgL−1 and 2.9–200μgL−1 for AMI, and in the range 0.9–200μgL−1, 2.5–200μgL−1 and 3.0–200μgL−1 for DOX in water, urine and plasma samples, respectively; the coefficients of determination were also equal to or higher than 0.9976. The inter- and intra-assay precisions (RSD%, n=3) were in the range of 2.8–3.4% and 2.9–3.9% at the three concentration levels of 5, 25 and 50μgL−1, respectively. Finally, under the optimal conditions, the method was applied for the analysis of the drugs in human urine and plasma pretreated samples and good results were obtained.
Clinical and preclinical studies suggest that hippocampal astrocyte dysfunction is involved in the pathophysiology of depression; however, the underlying molecular mechanisms remain unclear. Here, we ...attempted to identify the hippocampal astrocytic transcripts associated with antidepressant effects in a mouse model of depression. We used a chronic corticosterone-induced mouse model of depression to assess the behavioral effects of amitriptyline, a tricyclic antidepressant. Hippocampal astrocytes were isolated using fluorescence-activated cell sorting, and RNA sequencing was performed to evaluate the transcriptional profiles associated with depressive effects and antidepressant responses. Depression model mice exhibited typical depression-like behaviors that improved after amitriptyline treatment; the depression group mice also had significantly reduced GFAP-positive astrocyte numbers in hippocampal subfields. Comprehensive transcriptome analysis of hippocampal astrocytes showed opposing responses to amitriptyline in depression group and control mice, suggesting the importance of using the depression model. Transcription factor 7 like 2 (TCF7L2) was the only upstream regulator gene altered in depression model mice and restored in amitriptyline-treated depression model mice. In fact, TCF7L2 expression was significantly decreased in the depression group. The level of TCF7L2 long non-coding RNA, which controls mRNA expression of the TCF7L2 gene, was also significantly decreased in this group and recovered after amitriptyline treatment. The Gene Ontology biological processes associated with astrocytic TCF7L2 included proliferation, differentiation, and cytokine production. We identified TCF7L2 as a gene associated with depression- and antidepressant-like behaviors in response to amitriptyline in hippocampal astrocytes. Our findings could provide valuable insights into the mechanism of astrocyte-mediated antidepressant effects.
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized ...placebo-controlled trial was to evaluate a novel compounded topical gel for this problem.
Methods
Patients with CIPN were randomized to baclofen 10 mg, amitriptyline HCL 40 mg, and ketamine 20 mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4 weeks.
Results
Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (
p
= 0.053) and motor subscales (
p
= 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity.
Conclusion
Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.
A nanocomposite of Ce-doped ZnO/r-GO was synthesized using a conventional hydrothermal method. The synthesized nanocomposites were utilized for the purpose of sensitive and selective detection of ...cyclobenzaprine hydrochloride (CBP). The properties of the composite were extensively analyzed, including its morphology, structure, and electrochemical behavior. This study investigates the application of a modified glassy carbon electrode for the detection of CBP, a muscle relaxant used to treat musculoskeletal diseases that cause muscle spasms. The electrode is modified with Ce-doped ZnO/r-GO. Various detection methods, such as cyclic voltammetric and square wave techniques (SWV), were utilized. The composite material showed high effectiveness as an electron transfer mediator in the oxidation of CBP. The electrode showed a good response for SWV evaluations in CBP identification, with a minimum detection limit of 1.6 × 10
−
8
M and a wide linear range from 10 × 10
−
6
M to 0.6 × 10
−
7
M, under ideal conditions. The rate constant for charge transfer (ks) and the estimation of the electrochemical active surface area were obtained. A developed sensor exhibited desirable selectivity, long-lasting stability, and remarkable reproducibility. A sensor was used to analyze water, human serum, and urine samples, resulting in positive recovery results.
Graphical Abstract
This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the ...two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug.
A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC
, AUC
), the peak plasma concentration (C
), the time to achieve C
(T
), and the elimination half-life (t
). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs).
The values of t
and T
for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of C
, AUC
, and AUC
between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events.
This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption.
We previously reported that serotonin and norepinephrine reuptake inhibitors, amitriptyline (AMT) and imipramine (IMP), restored hypoglycemia awareness in rodents. To test the hypothesis that AMT and ...IMP could prevent the development of an impaired counterregulatory response (CRR) to hypoglycemia, Sprague-Dawley rats (250-350 g) with pre-implanted arterial and jugular cannulae were randomly assigned to one of four treatment groups: 1) recurrent saline controls (RS, n=8); 2) recurrent insulin-induced hypoglycemia (RH, 30-50 mg/dl, n=8); 3) RH + AMT (10 mg/kg IP, n=8); or 4) RH + IMP (5 mg/kg IP, n=8). Following 3-days of RS/RH treatment, all groups underwent 90-minute hyperinsulinemic (50 mU.kg-1.min-1) hypoglycemic (40-45 mg/dL) clamps. Blood glucose was similar for all groups during the clamp. Glucose infusion rates during the last 30-minutes were significantly reduced for both RH+AMT (23.7 mg/kg/min) and RH+IMP (24.8 mg/kg/min) as compared to RH (40.4 mg/kg/min), indicating that both drugs improved the glucoregulatory response to hypoglycemia. In conclusion, these studies identify 1) the involvement of serotonin and norepinephrine neurotransmitter pathways in the development of blunted counterregulatory responses to hypoglycemia, 2) in subjects with blunted CRR, these drugs may be useful therapeutic agents to improve the glucoregulatory response to hypoglycemia.
Disclosure
E.L.Macon: None. M.H.Devore: None. A.Iles: None. L.A.Schoeder: None. B.Patel: None. M.B.Music: None. S.Fisher: None.
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK118082)
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