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- Doxepin Rinse Versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Head and Neck Radiotherapy With or Without Chemotherapy: A Phase III, Randomized, Double-Blind Trial (NCCTG-N09C6 [Alliance]). [JOURNAL ARTICLE]
- J Clin Oncol 2014 Apr 14.
Painful oral mucositis (OM) is a significant toxicity during radiotherapy for head and neck cancers. The aim of this randomized, double-blind, placebo-controlled trial was to test the efficacy of doxepin hydrochloride in the reduction of radiotherapy-induced OM pain.In all, 155 patients were randomly allocated to a doxepin oral rinse or a placebo for the treatment of radiotherapy-related OM pain. Patients received a single dose of doxepin or placebo on day 1 and then crossed over to receive the opposite agent on a subsequent day. Pain questionnaires were administered at baseline and at 5, 15, 30, 60, 120, and 240 minutes. Patients were then given the option to continue doxepin. The primary end point was pain reduction as measured by the area under the curve (AUC) of the pain scale using data from day 1.Primary end point analysis revealed that the AUC for mouth and throat pain reduction was greater for doxepin (-9.1) than for placebo (-4.7; P < .001). Crossover analysis of patients completing both phases confirmed that patients experienced greater mouth and throat pain reduction with doxepin (intrapatient changes of 4.1 for doxepin-placebo arm and -2.8 for placebo-doxepin arm; P < .001). Doxepin was associated with more stinging or burning, unpleasant taste, and greater drowsiness than the placebo rinse. More patients receiving doxepin expressed a desire to continue treatment than did patients with placebo after completion of each of the randomized phases of the study.A doxepin rinse diminishes OM pain. Further studies are warranted to determine its role in the management of OM.
- Design, development and characterization of buccal bioadhesive films of Doxepin for treatment of odontalgia. [JOURNAL ARTICLE]
- Drug Deliv 2014 Mar 27.
Abstract Tricyclic antidepressants, as doxepin hydrochloride (DH), may have analgesic local effect due to its biochemical mechanism of action. Delivery of DH directly to the oral cavity could be an interesting alternative for toothache due to its analgesic local effect. One problem associated with the mucosal administration routes is the short residence time of the dosage form on the mucosal membranes. In this sense, we have developed new doxepin mucoadhesive films able of reducing pain and increasing the effectiveness of treatment. For this purpose, we tested three different polymers: chitosan, sodium hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (SCMC) in film elaboration. The results obtained show that all films are hydrophilic matrices that absorb water when placed in an aqueous media. All the films hydrated very quickly, reaching high percentage of swelling after just few minutes (5 min for SCMC, 2 min for HPMC and 30 min for chitosan). Moreover, the SCMC and HPMC films were dissolved whereas chitosan was not dissolved. Dissolution also leads to viscous liquids with a higher retention time over mucosal surfaces what may lead to adhesive interactions. In vitro permeation studies showed that for all the formulations studied, SCMC (19.91%), HPMC (69.5%) and chitosan (24.17%), the percentage of drug permeated increased compared to the drug solution (8.26%). Specifically the HPMC film presents greater amounts of doxepin permeated (49.27 ± 4.47 µg/cm(2)).
- Development of microextraction by packed sorbent for toxicological analysis of tricyclic antidepressant drugs in human oral fluid. [Journal Article]
- J Chromatogr A 2014 Apr 11.:9-16.
The aim of this study was to apply microextraction by packed sorbent (MEPS) to the isolation of six tricyclic antidepressants (TCADs): nordoxepin, doxepin, desipramine, nortriptyline, imipramine, and amitriptyline from human oral fluid. Samples were collected from healthy volunteers via free spillage from the oral cavity to disposable test tubes. A method of oral fluid sample pretreatment was developed and optimized in terms of suitability for MEPS extraction and removing of interfering agents (protein, food debris, or air bubbles). Moreover, it was short and simple to perform with limited sample consumption (150μL). Extracts were analysed by UHPLC-MS. The MEPS/UHPLC-MS method was validated at three concentration levels (2.00, 4.00 and 8.00ng/mL) of all analytes in the range 1.25-10.0ng/mL. The following parameters were determined: limit of detection, limit of quantification, precision, and accuracy. For all tested concentration levels, the intra- and inter-day repeatability did not exceeded 8.1% and 12.2%, respectively. Gained LOQ value, 0.50ng/mL, made the MEPS/UHPLC-MS method to be a useful tool in clinical and forensic laboratories, which was demonstrated on the basis of analysis of real samples.
- Contact allergens in oral antihistamines. [Journal Article]
- Dermatitis 2014 Mar-Apr; 25(2):83-8.
Excipients in various formulations of active drugs occasionally include known contact allergens. Their ingestion may trigger dermatitis or cause it to become widespread or refractory to therapy.The aim of this study was to investigate the prevalence of common contact allergens among the excipients of oral antihistamines available in this country.We gathered the complete ingredient lists of 2119 different preparations of 12 oral antihistamines from the National Library of Medicine data bank and entered them into an electronic database for analysis.More than half the formulations (55.0%) contained at least 1 member of the 10 allergen families assessed. Most brompheniramine and doxepin preparations included potentially allergenic excipients, whereas fexofenadine was most often free of them. Sorbitan group members, azo dyes, and propylene glycol were the allergens found most frequently in the antihistamines, each present in over 25% of the products. Elixirs, liquids, solutions, suspensions, and syrups were more likely than nonchewable caplets, capsules, and tablets to contain the allergens tabulated (100% vs 39.3%, respectively). Chewable pills frequently contained azo dyes.Ingestion of antihistamines could precipitate a systemic contact dermatitis in a patient sensitized to an allergen present as an excipient in the medicine.
- Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies. [Journal Article, Research Support, Non-U.S. Gov't]
- Pharmacol Rep 2013; 65(6):1611-21.
The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain. We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However, evidence from basic science is needed to improve our understanding of the mechanisms of action and their possible pharmacodynamic interactions.
- National use of prescription medications for insomnia: NHANES 1999-2010. [Journal Article, Research Support, N.I.H., Extramural]
- Sleep 2014 Feb; 37(2):343-9.
To determine current patterns and predictors of use of prescription medications commonly used for insomnia (MCUFI) in the U.S.Cross-sectional study.National Health and Nutrition Examination Survey, 1999-2010.32,328 noninstitutionalized community-dwelling U.S. adults.N/A.WE DEFINED MCUFI USE AS USE OF ANY OF THE FOLLOWING MEDICATIONS IN THE PRECEDING MONTH: benzodiazepine receptor agonists (eszopiclone, zaleplon, zolpidem, estazolam, flurazepam, quazepam, temazepam, triazolam), barbiturates (amobarbital, amobarbitalsecobarbital, chloral hydrate), doxepin, quetiapine, ramelteon, and trazodone. We estimated prevalence of MCUFI use and concurrent use of another sedating medication. We determined predictors of MCUFI use using multivariate logistic regression. Overall, 3% percent of adults used a MCUFI within the preceding month. Zolpidem and trazodone were used most commonly. Overall MCUFI use increased between 1999-2000 and 2009-2010 (P value for trend < 0.001). Concurrent use of other sedating medications was high, with 55% of MCUFI users taking at least one other sedating medication and 10% taking ≥ 3 other sedating medications. Concurrent use of MCUFIs with opioids (24.6%) and non-MCUFI benzodiazepines (19.5%) were most common. After adjustment, adults seeing a mental health provider (aOR 4.68, 95% C.I. 3.79, 5.77), using other sedating medications (aOR 4.18, 95% C.I. 3.36, 5.19), and age ≥ 80 years (aOR 2.55, 95% C.I. 1.63, 4.01) had highest likelihood of MCUFI use.In this nationally representative sample, reported use of prescription medications commonly used for insomnia (MCUFIs) within the preceding month was common, particularly among older adults and those seeing a mental health provider, with high use of sedative polypharmacy among MCUFI users.
- Amitriptyline, clomipramine, and doxepin adsorption onto sodium polystyrene sulfonate. [Journal Article]
- Daru 2014; 22(1):21.
Comparative in vitro studies were carried out to determine the adsorption characteristics of 3 drugs on activated charcoal (AC) and sodium polystyrene sulfonate (SPS). Activated charcoal (AC) has been long used as gastric decontamination agent for tricyclic antidepressants (TCA).Solutions containing drugs (amitriptyline, clomipramine, or doxepin) and variable amount of AC or SPS were incubated for 30 minutes.At pH 1.2 the adsorbent: drug mass ratio varied from 2 : 1 to 40 : 1 for AC, and from 0.4 : 1 to 8 : 1 for SPS. UV-VIS spectrophotometer was used for the determination of free drug concentrations. The qmax of amitriptyline was 0.055 mg/mg AC and 0.574 mg/mg SPS, qmax of clomipramine was 0.053 mg/mg AC and 0.572 mg/mg SPS, and qmax of doxepin was 0.045 mg/mg AC and 0.556 mg/mg SPS. The results of adsorption experiments with SPS revealed higher values for the qmax parameters in comparison with AC.In vitro gastric decontamination experiments for antidepressant amitriptyline, clomipramine, and doxepin showed that SPS has higher qmax values than the corresponding experiments with AC. Therefore, we suggest SPS is a better gastric decontaminating agent for the management of acute TCA intoxication.
- A case of neurodermatitis circumscipta of scalp presenting as patchy alopecia. [Journal Article]
- Int J Trichology 2013 Apr; 5(2):94-6.
Neurodermatitis or Lichen simplex chronicus (LSC) is chronic skin disease in which emotional factors have a key role in the initiation of disease. A sixty year old lady presented with itcy lesion of scalp with localised area of loss of hair. After proper history taking and investigations she was diagnosed as LSC of scalp. She was treated with intralesional steroids,oral doxepin and psychotherapy. Complete remission of symptoms with total regrowth of hair occured in 3 months. The key role of emotional factors in causation of LSC and a proper psychotherapy along with dermatological treatment is necessary for complete cure of this condition.
- Antidepressants for smoking cessation. [Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't]
- Cochrane Database Syst Rev 2014.:CD000031.
There are at least three reasons to believe antidepressants might help in smoking cessation. Firstly, nicotine withdrawal may produce depressive symptoms or precipitate a major depressive episode and antidepressants may relieve these. Secondly, nicotine may have antidepressant effects that maintain smoking, and antidepressants may substitute for this effect. Finally, some antidepressants may have a specific effect on neural pathways (e.g. inhibiting monoamine oxidase) or receptors (e.g. blockade of nicotinic-cholinergic receptors) underlying nicotine addiction.The aim of this review is to assess the effect and safety of antidepressant medications to aid long-term smoking cessation. The medications include bupropion; doxepin; fluoxetine; imipramine; lazabemide; moclobemide; nortriptyline; paroxetine; S-Adenosyl-L-Methionine (SAMe); selegiline; sertraline; St. John's wort; tryptophan; venlafaxine; and zimeledine.We searched the Cochrane Tobacco Addiction Group Specialised Register which includes reports of trials indexed in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and PsycINFO, and other reviews and meeting abstracts, in July 2013.We considered randomized trials comparing antidepressant medications to placebo or an alternative pharmacotherapy for smoking cessation. We also included trials comparing different doses, using pharmacotherapy to prevent relapse or re-initiate smoking cessation or to help smokers reduce cigarette consumption. We excluded trials with less than six months follow-up.We extracted data and assessed risk of bias using standard methodological procedures expected by the Cochrane Collaboration.The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline, expressed as a risk ratio (RR). We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed-effect model.Twenty-four new trials were identified since the 2009 update, bringing the total number of included trials to 90. There were 65 trials of bupropion and ten trials of nortriptyline, with the majority at low or unclear risk of bias. There was high quality evidence that, when used as the sole pharmacotherapy, bupropion significantly increased long-term cessation (44 trials, N = 13,728, risk ratio [RR] 1.62, 95% confidence interval [CI] 1.49 to 1.76). There was moderate quality evidence, limited by a relatively small number of trials and participants, that nortriptyline also significantly increased long-term cessation when used as the sole pharmacotherapy (six trials, N = 975, RR 2.03, 95% CI 1.48 to 2.78). There is insufficient evidence that adding bupropion (12 trials, N = 3487, RR 1.9, 95% CI 0.94 to 1.51) or nortriptyline (4 trials, N = 1644, RR 1.21, 95% CI 0.94 to 1.55) to nicotine replacement therapy (NRT) provides an additional long-term benefit. Based on a limited amount of data from direct comparisons, bupropion and nortriptyline appear to be equally effective and of similar efficacy to NRT (bupropion versus nortriptyline 3 trials, N = 417, RR 1.30, 95% CI 0.93 to 1.82; bupropion versus NRT 8 trials, N = 4096, RR 0.96, 95% CI 0.85 to 1.09; no direct comparisons between nortriptyline and NRT). Pooled results from four trials comparing bupropion to varenicline showed significantly lower quitting with bupropion than with varenicline (N = 1810, RR 0.68, 95% CI 0.56 to 0.83). Meta-analyses did not detect a significant increase in the rate of serious adverse events amongst participants taking bupropion, though the confidence interval only narrowly missed statistical significance (33 trials, N = 9631, RR 1.30, 95% CI 1.00 to 1.69). There is a risk of about 1 in 1000 of seizures associated with bupropion use. Bupropion has been associated with suicide risk, but whether this is causal is unclear. Nortriptyline has the potential for serious side-effects, but none have been seen in the few small trials for smoking cessation.There was no evidence of a significant effect for selective serotonin reuptake inhibitors on their own (RR 0.93, 95% CI 0.71 to 1.22, N = 1594; 2 trials fluoxetine, 1 paroxetine, 1 sertraline) or as an adjunct to NRT (3 trials of fluoxetine, N = 466, RR 0.70, 95% CI 0.64 to 1.82). Significant effects were also not detected for monoamine oxidase inhibitors (RR 1.29, 95% CI 0.93 to 1.79, N = 827; 1 trial moclobemide, 5 selegiline), the atypical antidepressant venlafaxine (1 trial, N = 147, RR 1.22, 95% CI 0.64 to 2.32), the herbal therapy St John's wort (hypericum) (2 trials, N = 261, RR 0.81, 95% CI 0.26 to 2.53), or the dietary supplement SAMe (1 trial, N = 120, RR 0.70, 95% CI 0.24 to 2.07).The antidepressants bupropion and nortriptyline aid long-term smoking cessation. Adverse events with either medication appear to rarely be serious or lead to stopping medication. Evidence suggests that the mode of action of bupropion and nortriptyline is independent of their antidepressant effect and that they are of similar efficacy to nicotine replacement. Evidence also suggests that bupropion is less effective than varenicline, but further research is needed to confirm this finding. Evidence suggests that neither selective serotonin reuptake inhibitors (e.g. fluoxetine) nor monoamine oxidase inhibitors aid cessation.
- Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine: analysis of therapeutic drug monitoring data under naturalistic conditions. [JOURNAL ARTICLE]
- Int Clin Psychopharmacol 2013 Dec 26.
Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these sample with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman's ρ r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed.