The pharmacokinetics of orally administered doxepin (50 mg) was studied in 8 healthy volunteers. Doxepin (DOX) and desmethyldoxepin (DDOX) concentrations in serum (or plasma) and red blood cells (RBCs) were measured by radioimmunoassay. Peak serum concentrations of DOX were observed at 1-2 hours and they ranged between 59.1-107.4 nmol/1. DOX disappearance was biphasic with a mean distribution half-life of 2.0 hrs and elimination half-life of 17.9 hrs. The mean total apparent volume of distribution was 22.7 l/kg and plasma clearance 0.93 l/hr/kg. The estimated mean first-pass metabolism of DOX was 71% assuming complete absorption. Peak DDOX concentrations were observed at 1-6 hours and they ranged between 35.0-117.8 nmol/l. DDOX elimination was monophasic with a mean apparent half-life of 28.5 hours. Equilibrium dialysis gave a mean protein binding of 75.5% for DOX and 76.0% for DDOX. A highly time dependent and interindividually variable RBC/plasma concentration ratio was observed for both substances. Initially the plasma concentrations were 3-4 times higher than the respective RBC concentrations, but at later time points more DOX and DDOX could be found from the RBCs than from plasma. The major reason for this seemed to be a slower elimination of both drugs from the erythrocytes than from plasma.
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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.
The fatal toxicity index (FTI) is the absolute number of fatal poisonings caused by a particular drug divided by its consumption figure. Consequently, it is a useful measure in evaluating toxicity of the drug and its relevance in fatal poisonings. In this study, we assessed the FTI of medicinal drugs in 3 years (2005, 2009, and 2013) in Finland. As the measure of drug consumption, we used the number of defined daily doses (DDD) per population in each year. There were 70 medicinal drugs in Finland for which the mean FTI expressed as the number of deaths per million DDD over the three study years was higher or equal to 0.1. The Anatomical Therapeutic Chemical (ATC) classification system was used for the classification of the active ingredients of medicinal drugs according to the organ or system which they act on. Of these 70 drugs, 55 drugs (78.6 %) acted on the nervous system (denoted by ATC code N), 11 (15.7 %) on the cardiovascular system (C), three (4.3 %) on the alimentary tract and metabolism (A), and one (1.4 %) on the musculoskeletal system (M). The nervous system drugs consisted of 20 psycholeptics, (ATC code N05), 20 psychoanaleptics (N06), eight analgesics (N02), six antiepileptics (N03), and one other nervous system drug (N07). The highest individual FTIs were associated with the opioids methadone, dextropropoxyphene, oxycodone, tramadol, and morphine; the antipsychotics levomepromazine and chlorprothixene; and the antidepressants doxepin, amitriptyline, trimipramine, and bupropion. Buprenorphine was not included in the study, because most of the fatal buprenorphine poisonings were due to smuggled tablets. A clearly increasing trend in FTI was observed with pregabalin and possibly with bupropion, both drugs emerging as abused substances.
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The prevalence of antidepressant drug use is higher than previously reported for other European countries. The preferred use of St. John's wort and tricyclics over SSRIs and other modern-type antidepressants in Germany is quite unique in Europe and different from the US. The identified drug use pattern leaves a major room for improvement in view of the numerous single prescription items purchased.
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The tricyclic antidepressant doxepin, representing a 5:1 mixture of trans- and cis-isomers, owns tranquilizing properties. This compound has been associated with illicit medication of racing horses, and therefore should be considered in doping control. Because analysis of doxepin in equine body fluids has not been documented in the literature, a highly sensitive analytical method was developed to individually monitor the doxepin isomers in blood and urine of horses by the use of gas chromatography/mass spectrometry. Following a dose of 1 mg doxepin-HCl/kg intravenously (i.v.), both the isomers were quantified for up to 24 h in serum of horses (n=4). The beta-half-lives of the trans- and cis-isomers were 3.5 and 3.1 h, respectively. The ratio of the trans/cis-isomers was found to be constant (4.7:1) during drug elimination and thus corresponded to the original composition of the antidepressant. Up to 12 h following administration low trans-isomer concentrations in an average range of 2-6 ng/mL were detected in urine of each of the horses, while the cis-isomer was only present in two of four horses for up to 8 and 12 h, respectively. In serum, mean trans-isomer concentrations exceeded urine levels maximally 120-fold after 3 h and at least sixfold after 12 h. As serum exhibits considerably higher concentrations of the doxepin isomers as compared with urine, blood of horses is the recommended body fluid when screening for the antidepressant.
This study was conducted in order to investigate the inhibition of synaptosomal 45calcium uptake by oxaprotiline, trimipramine and doxepin stereoisomers in the rat cingulate cortex which is an associative area of the cortex that interacts with the limbic system. A concentration-dependent inhibition of net depolarization-induced 45calcium uptake was observed for all substances tested. No significant difference in potency could be established within any of the pairs of antipodes and the IC50 values obtained were in the 30 microM to 50 microM range. These results are quite similar to those previously obtained with this group of compounds in hippocampal synaptosomes where discrepancies between relative calcium channel antagonism and clinical activity of the antipodes have been identified. Therefore, the present study of stereoisomers of tricyclic antidepressants fails to resolve these discrepancies and does not provide unequivocal support for the hypothesis that calcium channel blockade is somehow responsible for the therapeutic effect of tricyclic antidepressants.
This study provides a glimpse into the diagnostic and therapeutic approaches of senior dermatologists.
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Subjects were 12 female AN patients, 12 healthy female subjects, and 11 healthy male subjects. Positron emission tomography with H1R radioligand [(11)C]doxepin was performed on all subjects and regions of interest based analysis was conducted to evaluate brain H1R binding potential (BP). Abnormal eating behavior, depression, and anxiety of subjects were evaluated using the Eating Attitude Test-26 (EAT-26), Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI), respectively.
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Plasma levels of doxepin and its metabolite desmethyldoxepin were determined in 7 depressed patients treated with doxepin hydrochloride in 3 divided doses at 1000, 1600, and 2200 hours (t.i.d.), and repeated after changing the dosage schedule to a single daily bedtime (h.s.) dose at 2200 hours. Doxepin and its metabolite were measured at 9000, 1200, 1500, and 1800 hours. None of the individual patients showed clinically significant changes in their plasma concentration of tricyclic antidepressant on the 2 dosage schedules. No difference in the clinical condition of the patients was detected on the 2 dosage schedules using the Zung Self Rating Depression Scale, however patients experienced more morning sedation while on the single h.s. dosage. This study provides pharmacological support for the prescription of doxepin on a once daily basis.
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Cases were slightly less likely than controls to have filled two antidepressant prescriptions (primarily for doxepin, amitriptyline, or imipramine) in any 6-month period prior to a reference date set 1.5 years before diagnosis (conditional odds ratio (OR) 0.71, 95% confidence interval (CI) 0.47-1.1), or to have used an antidepressant continuously for 6 months or longer (OR 0.64, 95% CI 0.36-1.1). Cases were less likely than controls to have filled two benzodiazepine prescriptions in 6 months (OR 0.70, 95% CI 0.47-1.0) or to have used benzodiazepines continuously for 6 months or longer (OR 0.53, 95% Cl 0.15-1.9).
Doxepin is a tricyclic compound that has been used extensively for the treatment of depressive and anxiety disorders for approximately thirty years. It was noted early to have sedative effects and assist with the improvement of disrupted sleep patterns, but in higher antidepressant doses it was also noted to have significant anticholinergic and antinoradrenergic properties. These properties led to significant dose-limiting side effects, which at times precluded its effective use. Recently, doxepin has seen renewed interest in low doses as an H1 specific antagonist in sleep disorders.
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GPs in Germany often prescribe medications that have been designated as potentially inappropriate to their elderly patients with GAD - especially those with comorbid depressive disorders. Further research is needed to ascertain whether there are specific subgoups of elderly patients with GAD for whom the benefits of these medications outweigh their risks.
A systematic screening method has been developed for the detection of 29 central nervous system (CNS) drugs in human plasma, urine and gastric juice by high performance capillary electrophoresis (HPCE). The first step is sample preparation. The patient's or normal human plasma (0.5 ml) spiked with CNS drugs was extracted with 2 x 4 ml dichloromethane, while 2 ml of patient's or spiked urine was extracted with 2 x 6 ml chloroform. The combined extract from plasma or urine was evaporated to dryness in a rotation evaporator at 35 degrees C. The residue was dissolved in 100 microliters methanol and subsequently 400 microliters of redistilled water was added. The patient gastric juice (3 ml) was centrifuged at 2,000 r.min-1 for 5 min. The supernatant was filtered through 0.45 micron microporous membrane for injection onto capillary columns. The second step was to perform CZE separation in acidic buffer composed of 30 mmol.L-1(NH4)3PO4(pH 2.50) and 10% acetonitrile (condition A). Most of the benzodiazepines (diazepam, nitrazepam, chlordiazepoxide, flurazepam, extazolam, alprazolam) and methaqualone were baseline separated and detected at 5-13 min, while thiodiphenylamines showed group peaks at 3-5 min and barbiturates migrate with electroosmotic fluid (EOF) together. The third step is to separate the drugs in basic buffer constituted of 70 mmol.L-1 Na2HPO4(pH 8.60) and 30% acetonitrile (condition B). The thiodiphenylamines and some other basic drugs could be well separated, which include thihexyphenidyl, imipramine, amitriptyline, diphenhydramine, chlorpromazine, doxepin, chlorprothixene, promethazine and flurazepam, while the rest of the CNS drugs did not interfere with the separation. The last step was to separate the drugs by micellar electrokinetic chromatography (MEKC) in such a buffer as 70 mmol.L-1 SDS plus 15 mmol.L-1 Na2HPO4 (pH 7.55) and 5% methanol (condition C). Barbiturates (barbital, phenobarbital, methylphenobarbital, amobarbital, thiopental, pentobarbital, secobarbital) and some hydrophobic drugs (glutethimide, alprazolam, clonazepam, carbamazepine, trifluoperazine, oxazepam) could be well separated. These drugs might be identified by both the relative migration time (rtm = tdrug/tEOF) and the ratios of peak heights (rh) monitored at different wavelength, since the ratios are characteristic of the spectrum of a drug. This method has been used in several real clinical samples of intoxication. For example, perphenazine and doxepin were detected in the gastric juice and phenobarbital in blood and gastric juice of an intoxicated patient.
The kinetics of protriptyline were examined in 8 subjects after a single oral dose of 30 mg protriptyline hydrochloride. Peak protriptyline levels ranged from 10.4 to 22.3 ng/ml and were reached 6 to 12 hr after the oral dose. The mean protriptyline half-life (t1/2) was 74.3 hr and ranged from 53.6 to 91.7 hr in individual subjects, confirming the long t1/2 of protriptyline reported by Moody and associates. The estimated first-pass metabolism of protriptyline was relatively small, ranging from 10% to 25% of the oral dose, assuming complete absorption. The mean volume of distribution was 22.5 L/kg and ranged from 15.0 to 31.2 L/kg. No relationship was found between the kinetics of protriptyline and those of doxepin studied previously in 7 of the 8 subjects.
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A method based on poly (methacrylic acid-co-ethylene glycol dimethacrylate) monolith microextraction and octadecylphosphonic acid-modified zirconia-coated CEC followed by field-enhanced sample injection preconcentration technique was proposed for sensitive CE-UV analysis of six antidepressants (doxepin, clozapine, imipramine, paroxetine, fluoxetine and chlorimipramine) in human plasma and urine. A poly(methacrylic acid-co-ethylene glycol dimethacrylate) monolithic capillary column was introduced for the extraction of antidepressants from urine and plasma samples. The hydrophobic main chains and acidic pendant groups of the monolithic column make it a superior material for extraction of basic analytes from aqueous matrix. After extraction, the desorption solvent, which normally provided an excellent medium to ensure direct compatibility for field-enhanced sample injection in CE, was analyzed by CE directly. By the use of alkylphosphonate-modified zirconia-coated CEC for separation of the basic compounds of antidepressants, high separation efficiency and resolution were achieved because that both hydrophobic interaction between analytes and alkylphosphonate-modified zirconia coat and electrophoretic effect work on the separation of antidepressants. The best separation was achieved using a buffer composed of 0.3 M ammonium acetate (adjusted to pH 4.5 with 1 M acetic acid) and 35% ACN v/v, with a temperature and voltage of 20 degrees C and 20 kV, respectively. By applying both preconcentration procedures, LODs of 11.4-51.5 and 3.7-17.0 microg/L were achieved for the six antidepressants in human plasma and urine, respectively. Excellent method of reproducibility was found over a linear range of 50-5000 microg/L in plasma and urine sample.
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A multi-residue method was developed that allows for the simultaneous determination of psychoactive compounds such as opioids, tranquilizers, antiepileptics (primidone, carbamazepine plus two metabolites),the cocaine metabolite benzoylecgonine, the antidepressant doxepin, as well as the calcium channel blocker verapamil in raw and treated wastewater, surface water, groundwater, and drinking water. After solid-phase extraction with Oasis HLB at neutral pH, the analytes were detected by LC electrospray tandem MS in the positive ion mode. With a few exceptions relative recoveries of the analytes exceeded 70%. The limits of quantification were in the low ng/L range. Matrix effects were compensated by using appropriate deuterated or 13C-15N-labeled surrogate standards. For raw and treated wastewater, concentration factors were lowered to reduce matrix effects. Most analytes (15 of 20) were found in raw and treated wastewater as well as in surface water, and hence, are presumably ubiquitously present in the environment. Antiepileptics, the opium alkaloids morphine and codeine, dihydrocodeine, the two tranquilizers oxazepam and temazepam, the opioid tramadol, doxepin, and verapamil were detected in STP discharges and German rivers at concentrations up to the microg/L range. In drinking water, only carbamazepine, its metabolite 10,11-dihydroxy-10,11-dihydrocarbamazepine, and primidone were present at concentrations up to 0.020 microg/L.
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161 general practitioners and 162 psychiatrists in private practice documented 1319 patients, receiving doxepin for individual clinical reasons. Physicians were randomly divided into a guideline exposed and a control group. All physicians treated their patients according to individual clinical considerations.
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The radiochemical yield (decay corrected) of (11)C-doxepin for clinical use was 47.0 ± 5.2% (n = 12) based on [(11)C]methyl iodide, moreover the radiochemical purity of (11)C-doxepin was more than 97.5% with 1,200 ± 500 Ci/mmol specific activity(end of production). The total production time of (11)C-doxepin was 37 min from end of bombardment (EOB) with the final product passing all tests under cGMP requirements for clinical use.
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The cases had taken dothiepin (16 patients), doxepin (six patients), thioridazine (five patients), amitriptyline (five patients), nortriptyline (three patients), imipramine (one patient) and a combination of dothiepin and thioridazine (three patients). In 20 of the 39 patients with arrhythmias, the arrhythmia had been a presumed ventricular tachycardia. Of the other 19 patients, 15 patients had a supraventricular tachycardia, two patients had cardiac arrests (one asystole, one without ECG monitoring) and two patients had insufficient data recorded to make classification of the arrhythmias possible. The QRS was >/= 100 ms in 82% of cases but also in 76% of controls. QRS >/= 160 ms had a sensitivity of only 13% and occurred in 2% of controls. QRS > 120 ms, QTc > 500 and the R/S ratio in aVR appeared to have a stronger association with the occurrence of arrhythmia: QRS > 120 ms (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.46-8.68), QTc > 500 (OR, 3.07; 95% CI, 1.33-7.07), and R/S ratio in aVR > 0.7 (OR, 16; 95% CI, 3.47-74). Excluding thioridazine overdoses and performing the analysis for tricyclic antidepressant overdoses alone gave increased odds ratios for QRS > 120 ms (OR, 4.83; 95% CI, 1.73-13.5) and QTc > 500 (OR, 4.5; 95% CI, 1.56-13) but had little effect on that for the R/S ratio in aVR > 0.7 (OR, 14.5; 95% CI, 3.10-68).
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Narcotic addicts may manifest symptoms of depression that aggravate their addiction. In this double-blind study of 35 mildly depressed patients in a methadone maintenance program, subjects who received doxepin improved significantly more than control subjects. Even in this short-term study, the reduction in depression was associated with a trend toward better performance in other areas of rehabilitation.
DXP 1 mg and 3 mg administered nightly to elderly chronic insomnia patients for 12 weeks resulted in significant and sustained improvements in most endpoints. These improvements were not accompanied by evidence of next-day residual sedation or other significant adverse effects. DXP also demonstrated improvements in both patient- and physician-based ratings of global insomnia outcome. The efficacy of DXP at the doses used in this study is noteworthy with respect to sleep maintenance and early morning awakenings given that these are the primary sleep complaints of the elderly. This study, the longest placebo-controlled, double-blind, polysomnographic trial of nightly pharmacotherapy for insomnia in the elderly, provides the best evidence to date of the sustained efficacy and safety of an insomnia medication in older adults.
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The mechanism(s) by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis remain elusive. The endocannabinoid system (eCBs) which exhibits antidepressant potential, appears to regulate the HPA axis activity. Therefore, we aimed to investigate the role of the eCBs in the action of doxepin including its effect on the HPA axis.
The propyl group of ropivacaine ( N -propyl-2',6'-pipecoloxylidide hydrochloride) could be responsible for conferring some sensory selectivity to this drug. Thus, adding a propyl group to experimental local anesthetics (LAs) (e.g., the tricyclic antidepressants amitriptyline and doxepin) to increase sensory selectivity may be useful. We, therefore, synthesized N -propyl amitriptyline and N -propyl doxepin and investigated a potential predominance of sensory/nociceptive block over motor block (differential block) in a rat sciatic nerve block model. In addition, tetrodotoxin (TTX), a naturally occuring Na + channel blocker, was coinjected to investigate whether it increased block duration.
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Sixty patients with chronic pain of the low back or cervical spine concomitant with clinical depression were studied in a 6-week, randomized, double-blind comparison of doxepin and placebo. Significant improvements in the doxepin-treated group compared to placebo or to baseline values were seen on Hamilton depression scores, Global Assessment Scale scores, pain severity, percent of time pain felt, and effect of pain on activity, sleep, and muscle tension. Some improvements were observed after 1 week of treatment; the most improvement occurred at 6 weeks, when the mean doxepin dosage was approximately 200 mg/day and plasma doxepin and nordoxepin averaged 80 ng/ml. No significant harmful effects were observed. Neither plasma beta-endorphin nor enkephalin-like activity demonstrated significant differences from baseline. These data indicate that doxepin is a valuable treatment for patients with chronic pain and depression.