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- Doxepin and diphenhydramine increased non-rapid eye movement sleep through blockade of histamine H1 receptors. [JOURNAL ARTICLE]
- Pharmacol Biochem Behav 2014 Dec 11.
Histaminergic neurons have been reported to play an important role in the regulation of sleep-wake behavior through the histamine H1 receptor (R, H1R). First generation H1R antagonists, such as doxepin and diphenhydramine, produce drowsiness in humans, and are occasionally used to treat insomnia. However, if H1R antagonists function via physically blocking the H1R remains unclear. In the current study, we used H1R knockout (KO) mice to investigate if the sleep-promoting effects of doxepin and diphenhydramine are dependent on blockade of the H1R. When doxepin was administered, non-rapid eye movement (NREM) sleep in wild type (WT) mice increased for 4 h, with an increase in the numbers of NREM sleep bouts of 256-512 s and 512-1024 s. These effects were not observed in the H1R KO mice. Furthermore, diphenhydramine increased NREM sleep for 6 h in WT, and not in the H1R KO mice after the injection. These results indicate that both doxepin at 15 mg/kg and diphenhydramine at 10 mg/kg induce NREM sleep through blockade of H1R.
- Brain histamine H1 receptor occupancy measured by PET after oral administration of levocetirizine, a non-sedating antihistamine. [JOURNAL ARTICLE]
- Expert Opin Drug Saf 2014 Dec 3.:1-8.
Objective:Histamine H1 receptor (H1R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H1R occupancy (H1RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.
Methods:Eight healthy volunteers underwent positron emission tomography (PET) imaging with [(11)C]doxepin, a PET tracer that specifically binds to H1Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H1ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.
Results:There was no significant difference between the mean brain H1RO after levocetirizine administration (8.1%; 95% CI: -9.8 to 26.0%) and fexofenadine administration (-8.0%; 95% CI: -26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H1RO of the two antihistamines.
Conclusion:At therapeutic dose, levocetirizine does not bind significantly to the brain H1Rs and does not induce significant sedation.
- The influence of microglia activation on the efficacy of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine in a rat model of neuropathic pain. [JOURNAL ARTICLE]
- Eur J Pharmacol 2014 Nov 25.
The analgesic properties of antidepressants are often used in the treatment of neuropathy, however their influence on glial cells in maintaining neuropathic pain is unknown. Our studies examined the neuropathic pain-relieving properties after intraperitoneal injection of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine 7 days after sciatic nerve injury (CCI) in rats and its influence on microglia/macrophages (IBA-1) and astroglia (GFAP) activation in the spinal cord and dorsal root ganglia (DRG) using Western blot. All tested antidepressants significantly reduced CCI-induced allodynia but hyperalgesia was only antagonized by fluoxetine, doxepine and venlafaxine. The strongest analgesia was observed after fluoxetine administration. A Western blot analysis shown the upregulation of the IBA-1 in the lumbar spinal cord and DRG after amitriptyline or milnacipran administration in CCI-exposed rats, whereas after fluoxetine the downregulation was observed. The administration of doxepin did not change the IBA-1 protein level in both studied structures, however venlafaxine decreased the IBA-1 only in the DRG. No changes in the GFAP level in both structures were observed after any of listed above antidepressants administration. Chronic minocycline treatment enhanced amitriptyline and milnacipran, but did not fluoxetine analgesia under neuropathic pain in rats. Our results suggest that nerve injury-induced pain is related with the activation of microglia, which is diminished by fluoxetine treatment in the neuropathic pain model.
- Transbuccal delivery of doxepin: Studies on permeation and histological investigation. [Journal Article]
- Int J Pharm 2014 Dec 30; 477(1-2):650-4.
According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79μg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24μg/cm(2)/μg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice.
- Use of ultra-low-dose (≤6 mg) doxepin for treatment of insomnia in older people. [Journal Article, Review]
- Can Pharm J (Ott) 2014 Sep; 147(5):281-9.
Insomnia is one of the most frequent complaints encountered in primary care practice, one that results in significant clinical consequences and cost burden to the public health system. It is more common in elderly adults (≥65 years of age), with frequent complaints regarding sleep maintenance and early morning wakening. Current treatment options have limitations. This review was conducted to evaluate the evidence behind ultra-low-dose doxepin in insomnia and to discuss its potential advantages, its place in therapy and its implications in practice in the treatment of older patients.A systematic literature search was conducted of MEDLINE via Ovid, PubMed and EMBASE using the MeSH and key terms "doxepin," "sleep initiation and maintenance disorders," "insomnia," and "low dose." Only randomized controlled trials comparing 3 mg and/or 6 mg of doxepin to placebo and involving participants diagnosed with primary insomnia were included. Primary outcomes for this review were objective sleep study parameters.Five studies were identified, 3 of which (n = 571) were conducted in older adults. Doxepin 3 mg and 6 mg significantly reduced waking after sleep onset and increased total sleep time. There was no significant difference between the 2 doses of doxepin. Latency to persistent sleep did not differ significantly compared with placebo for any doses of doxepin. The most frequent adverse events reported were somnolence and headache. Adverse events did not appear to be dose-related, and studies reported the incidence of adverse effects to be comparable to placebo.Doxepin 3 mg and 6 mg significantly improved and sustained sleep maintenance and sleep duration into the last third of the night but did not significantly affect sleep onset. Sleep benefits were achieved without next-day residual or discontinuation effects. Doxepin appears to be well suited for managing insomnia in older people.
- [Rapid screening and confirmation of antidepressants in blood using automated solid phase extraction and liquid chromatography-time-of-flight mass spectrometry]. [English Abstract, Journal Article]
- Se Pu 2014 Jul; 32(7):687-92.
A high-throughput method was developed for screening antidepressants in blood by automated solid phase extraction and liquid chromatography with high resolution quadrupole-time-of-flight mass spectrometry (ASPE-LC-Q-TOF/MS). The samples were cleaned up by an HLB solid phase extraction cartridge and analyzed by LC-Q-TOF/MS under electrospray ionization (ESI) mode with scanning range of m/z 50-1 000 Da. The chromatographic separation was performed on an Agilent Eclipse Plus C18 column (50 mm x 2.1 mm, 1.8 microm) with gradient elution using methanol and 5 mmol/L ammonium formate aqueous solution (containing 0.2% formic acid) as mobile phases. Rapid screening and confirmation can be achieved using MS matching scores, deviation of retention time, measured mass, isotopic abundance matching scores, isotope space matching scores and MS/MS matching scores. The quantitative analysis was carried out by correlating the extracting peak area with accurate mass. Good linearities were observed in the range of 1 - 500 microg/L with the correlation coefficients from 0.997 6 to 0.999 7. The limits of detection were 0.01-0.5 microg/L. The spiked recoveries were 79.6%-96.4% with the relative standard deviations of 4.1% - 6.4%. The result screening database was built using Agilent MassHunter PCDL Manager software and then used for the analysis of spiked samples. MS matching scores, isotopic abundance matching scores, isotope space matching scores (all > 95 points) and MS/MS matching scores (> 70 points) were applied to identify the analytes. The results showed that all the spiked antidepressants could be correctly identified with low deviation of retention time (< 0.1 min) and mass (< 1 mDa). The developed method was further applied for the analysis of poisoning cases, and amitriptyline, carbamazepine, doxepin were detected. In brief, the method is rapid, sensitive, simple, reliable, and suitable for the screening and confirmation of antidepressants in forensic and clinical analytical toxicology.
- Drug treatment of primary insomnia: a meta-analysis of polysomnographic randomized controlled trials. [Journal Article, Research Support, Non-U.S. Gov't]
- CNS Drugs 2014 Sep; 28(9):799-816.
Although insomnia is a frequent health complaint that is often treated with drugs, little is known about differences in treatment efficacy of various drug classes on objective versus subjective outcome measures.Our aim was to compare treatment efficacy of classical benzodiazepines, benzodiazepine receptor agonists (zopiclone, zolpidem and zaleplon), antidepressants (including low-dose doxepin), neuropeptides, progesterone receptor antagonists, hormones, melatonin receptor agonists, antihistamines, antiepileptics, and narcotics addressing primary insomnia.We conducted a comprehensive literature search (up to 5 April 2013) using PubMed, Cochrane Clinical Trials, PQDT OPEN, OpenGREY, ISI Web of Knowledge, PsycINFO, PSYNDEX, and the WHO International Clinical Trials Registry Platform.Only polysomnographic, parallel-group, randomized controlled drug trials were included; eligibility was determined by two independent authors.We used a random effects model, based on 31 studies reporting 80 treatment conditions, covering 3,820 participants.Effect size estimates for the total sample of pooled drug classes suggest that there is a small-to-moderate, significant, and robust effect for objective outcomes (sleep onset latency g = -0.36, total sleep time g = 0.27) and subjective outcomes (sleep onset latency g = -0.24, total sleep time g = 0.21). Results indicate higher effect sizes for benzodiazepine receptor agonists and classical benzodiazepines compared with antidepressants (including low-dose doxepin) and for classical benzodiazepines compared with benzodiazepine receptor agonists. Benzodiazepine receptor agonists demonstrated higher effect sizes for objective outcomes.Data on drug safety were not analyzed.Future studies should use objective and subjective assessment. Focusing on efficacy, clinicians should favor benzodiazepine receptor agonists and classical benzodiazepines over antidepressants (including low-dose doxepin) for primary insomnia treatment, but the additional consideration of different side effect profiles can lead to alternative treatment decisions.
- Doxepin for insomnia: A systematic review of randomized placebo-controlled trials. [REVIEW]
- Sleep Med Rev 2014 Jun 19.
Doxepin, a sedating tricyclic drug, at 3 mg and 6 mg doses was recently approved by the U.S. food and drug administration (FDA) for the treatment of insomnia. The objective of this systematic review was to obtain a precise summary of the efficacy and safety of doxepin as a hypnotic. We searched key databases and trial registers up to March 2014 and contacted pharmaceutical companies and the FDA for unpublished data. A total of nine randomized placebo-controlled trials were analyzed. Six studies were on doxepin 1-6 mg/d, two on doxepin 25-300 mg/d, and one on ramelteon 8 mg and doxepin 3 mg combined. All low-dose studies were industry-sponsored. We found that low-dose doxepin had a small to medium effect size against placebo for sleep maintenance and sleep duration but not for sleep initiation at both immediate and short-term posttreatment. There was no significant next-day residual effect with low-dose doxepin. Headache and somnolence were the most common side effects. We concluded that low-dose doxepin for 1-2 nights appeared to be safe and effective in improving sleep. However, a clear conclusion on its short-term benefits and risks as well as withdrawal effects was not possible due to the small number of studies.
- Topical treatments of skin pain: a general review with a focus on hidradenitis suppurativa with topical agents. [Journal Article]
- Dermatol Online J 2014 Jul; 20(7)
Hidradenitis Supprurativa (HS) is a painful chronic follicular disease. Few papers have addressed pain control for this debilitating condition. Possible topical agents include tricyclic antidepressants, opioids, anticonvulsants, NSAIDs, NMDA receptor antagonists, local anesthetics and other agents. The first line agents for the topical treatment of the cutaneous pain of HS are diclonefac gel 1% and liposomal xylocaine 4% and 5% cream or 5% ointment. The chief advantage of topical xylocaine is that is quick acting i.e. immediate however with a limited duration of effect 1-2 hours. The use of topical ketamine, which blocks n-methyl-D-aspartate receptors in a non-competitive fashion, might be a useful tool for the treatment of HS pain. Topical doxepin, which available in a 5% commercially preparation (Zonalon®) , makes patients drowsy and is not useful for controlling the pain of HS . Doxepin is available in a 3% or 3.3% concentration (which causes less drowsiness) from compounding pharmacies and can be used in compounded analgesic preparations with positive effect. Topical doxepin is preferred over use of topical amitriptyline because topical doxepin is more effective. Nevertheless, topical amitriptyline increase of the tactile and mechanical nociceptive thresholds and can be used for topical pain control in compound mixture of analgesics . Gabapentin and pregablin can also be used compounded with other agents in topical analgesic preparations with positive topical anesthetic effect. Capsaicin is not useful for topical treatment of the pain of HS. Sometimes compounded of anesthetics medications such as ketamine 10%, bupivacaine 1%, diclofenac 3%, doxepin 3% or 3.3%, and gabapentin 6% can extend the duration of effect so that medication only needs to be used 2 or 3 times a day. Still in my experience the easiest to get and most patient requested agent is topical diclonefac 1% gel.
- Eosinophilic folliculitis occurring after stem cell transplant for acute lymphoblastic leukemia: a case report and review. [JOURNAL ARTICLE]
- Int J Dermatol 2014 Jul 11.
Eosinophilic folliculitis (EF) comprises classic eosinophilic pustular folliculitis (EPF), human immunodeficiency virus (HIV)-related EF, and infantile EPF subtypes. A fourth proposed subtype describes EF associated with hematologic malignancy. Recently, EF has occurred after bone marrow or stem cell transplantation (SCT).We report a unique case of EF after haploidentical allogeneic SCT for acute lymphoblastic leukemia (ALL) and review the literature for similar cases.A 56-year-old, HIV-negative ALL patient presented with an intensely pruritic papulopustular eruption. He had undergone haploidentical allogeneic SCT 65 days earlier, which he had tolerated well. Histopathology revealed a moderately dense perifollicular and perivascular lymphocytic infiltrate with many eosinophils extending from the superficial dermis to the subcutaneous fat. Fungal stains were negative. These findings were highly consistent with EF.Therapy with a class II topical corticosteroid ointment, oral doxepin, and emollients achieved near-resolution of the lesions within eight weeks. Transition to topical tacrolimus 0.1% ointment applied twice daily to residual lesions yielded complete clearance by 12 weeks with mild post-inflammatory hyperpigmentation. The patient's ALL remains in remission.A fourth proposed subtype of EF is associated with HIV-negative hematologic disease. This subtype is distinguished by a predictable timeframe to presentation and a relatively rapid response to therapy. Although EF is an important consideration in all patients with hematologic malignancy, clinically heightened suspicion is warranted during the 2-3 months after transplant.