Administration Of Doxepin Research Articles

Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice

Doxepin is commonly prescribed for depression and anxiety treatment. Doxepin-related disruptions to metabolism and renal/hepatic adverse effects remain unclear; thus, the underlying mechanism of action warrants further research. Here, we investigated how doxepin affects lipid change, glucose homeostasis, chromium (Cr) distribution, renal impairment, liver damage, and fatty liver scores in C57BL6/J mice subjected to a high-fat diet and 5 mg/kg/day doxepin treatment for eight weeks. We noted that the treated mice had higher body, kidney, liver, retroperitoneal, and epididymal white adipose tissue weights; serum and liver triglyceride, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine levels; daily food efficiency; and liver lipid regulation marker expression. They also demonstrated exacerbated insulin resistance and glucose intolerance with lower Akt phosphorylation, GLUT4 expression, and renal damage as well as higher reactive oxygen species and interleukin 1 and lower catalase, superoxide dismutase, and glutathione peroxidase levels. The treated mice had a net-negative Cr balance due to increased urinary excretion, leading to Cr mobilization, delaying hyperglycemia recovery. Furthermore, they had considerably increased fatty liver scores, paralleling increases in adiponectin, FASN, PNPLA3, FABP4 mRNA, and SREBP1 mRNA levels. In conclusion, doxepin administration potentially worsens renal injury, nonalcoholic fatty liver disease, and diabetes.

Doxepin prevents the Expression and Development of Paclitaxel-Induced Neuropathic Pain.

Background:Peripheral neurotoxicity is a common side effect of many anticancer chemotherapy drugs, including paclitaxel. Peripheral neurotoxicity may present as changes in sensory function and mild paresthesia that, in turn, can lead to alleviation of the prescribed dose of the medication. The aim of this study was to evaluate the effectiveness of acute and chronic doxepin administration on development and expression of neuropathic pain during the treatment of cancer with paclitaxel.Materials and Methods:Neuropathic pain was induced in mice by paclitaxel (2 mg/kg, intraperitoneally [i.p.,] once daily from day 1 to day 5) that caused mechanical and cold allodynia. Doxepin was administrated every day from day 6 to 10 (10 and 15 mg/kg i.p.). Mechanical and cold allodynia was evaluated on day 11 of the experiment in both the test and the control group.Results:Daily administration of doxepin (2.5, 5, and 10 mg/kg i.p.) from day 1 to 5 significantly inhibited the development of cold and mechanical allodynia. As well doxepin administration (5 and 10 mg/kg i.p.) from the 6th day, to 10th day significantly inhibited cold and mechanical allodynia expression. To address the concerns associated with the effectiveness of chemotherapy agents on the tumor, we evaluated paclitaxel cytotoxicity effect in combination with doxepin. Our observations indicate that doxepin even at high concentrations (1 and 10 μg/ml) does not interfere with the cytotoxic effect of paclitaxel (0.05 μg/ml).Conclusions:These results indicate that doxepin, when administered during chemotherapy, can prevent the development and expression of paclitaxel-induced neuropathic pain.

Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway.

Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin’s effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.

Music electric stimulation of points for anxiety: a multi-center randomized controlled clinical trial

To observe the therapeutic efficacy of music electric stimulation of points in treating anxiety. By adopting a design of multi-centered randomized controlled trial (RCT), a total of 270 patients with anxiety were randomized into a treatment group and a medication group. The treatment group was intervened by music electric stimulation of points, while the medication group was intervened by oral administration of doxepin. The two groups were evaluated by using Hamilton anxiety rating scale (HAMA) and Chinese revised edition of self-rating anxiety scale (SAS-CR) before and after the intervention. The therapeutic efficacies were also compared. The total effective rate was 93.6% in the treatment group versus 92.3% in the medication group, and the between-group difference was statistically insignificant (P>0.05). After the treatment, the aggregate scores of HAMA and SAS-CR were significantly changed in both groups (both P 0.05). Music electric stimulation of points can produce equivalent efficacy in treating anxiety compared to doxepin. Thus, it can be taken as a choice in the treatment of anxiety.

Development of a mucoadhesive delivery system for control release of doxepin with application in vaginal pain relief associated with gynecological surgery

The main purpose of this study was to develop a semisolid mucoadhesive formulation for the non-invasive vaginal administration of doxepin (DOX) for relief of pain derived from the scarring process after surgery. An orafix® platform loading DOX was tested for adequate stability, rheology and vaginal mucoadhesion capacity. The formulation exhibited appropriate pH and was microbiologically stable. The rheological studies confirmed its pseudoplastic and thixotropic nature with prevalence of the elastic behavior component over the viscous one. Appropriate syringeability and spreadability results were also confirmed. Different experiments showed adequate mucoadhesion capacity even in the presence of simulated vaginal fluid. Finally, DOX release, permeation and retention in vaginal mucosa studies were also accomplished with promising results. DOX release kinetics followed the modified Higuchi model and the permeation studies did not render such high values as to suggest potential systemic absorption which could lead to undesirable systemic side effects. Therefore, we can hypostatize that the proposed formulation may assist to fill in the therapeutic gap regarding pure pain relief at local level in vagina.

Effects of chronic doxepin and amitriptyline administration in naïve mice and in neuropathic pain mice model

Neuropathic pain is a severe clinical problem, often appearing as a co-symptom of many diseases or manifesting as a result of damage to the nervous system. Many drugs and agents are currently used for the treatment of neuropathic pain, such as tricyclic antidepressants (TCAs). The aims of this paper were to test the effects of two classic TCAs, doxepin and amitriptyline, in naïve animals and in a model of neuropathic pain and to determine the role of cytokine activation in the effects of these drugs. All experiments were carried out with Albino-Swiss mice using behavioral tests (von Frey test and the cold plate test) and biochemical analyses (qRT-PCR and Western blot). In the mice subjected to chronic constriction injury (CCI), doxepin and amitriptyline attenuated the symptoms of neuropathic pain and diminished the CCI-induced increase in the levels of spinal interleukin (IL)-6 and -1β mRNA, but not the protein levels of these cytokines, measured on day 12. Unexpectedly, chronic administration of doxepin or amitriptyline for 12days produced allodynia and hyperalgesia in naïve mice. The treatment with these drugs did not influence the spinal levels of IL-1β and IL-6 mRNA, however, the protein levels of these pronociceptive factors were increased. The administration of ondansetron (5-HT3 receptor antagonist) significantly weakened the allodynia and hyperalgesia induced by both antidepressants in naïve mice; in contrast, yohimbine (α2-adrenergic receptors antagonist) did not influence these effects. Allodynia and hyperalgesia induced in naïve animals by amitriptyline and doxepin may be associated with an increase in the levels of pronociceptive cytokines resulting from 5-HT3-induced hypersensitivity. Our results provide new and important information about the possible side effects of antidepressants. Further investigation of these mechanisms may help to guide decisions about the use of classic TCAs for therapy.

The influence of microglia activation on the efficacy of amitriptyline, doxepin, milnacipran, venlafaxine and fluoxetine in a rat model of neuropathic pain

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 antagonised by fluoxetine, doxepine and venlafaxine. The strongest analgesia was observed after fluoxetine administration. Western blot analysis showed 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

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=0.49×10−3cm/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/cm2/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.

Effects of different doses of doxepin on passive avoidance learning in rats

Background:Studies have shown that Doxepin has anti-inflammatory effects and reduces oxidative stress. Due to the fact that other tricyclic antidepressants have been shown to have neuroprotective effects, this study aimed to investigate the effects of different doses of doxepin on passive avoidance learning in rats.Materials and Methods:Old male Wistar rats were used in this study. Doxepin was administered intraperitoneally (1, 5 and 10 mg/kg) for 21 days. Passive avoidance learning test was used for evaluation of learning and memory. Rats received foot electrical shock on fifteen day, and step through latencies were evaluated one week after the electrical shock in retention phase.Results:Administration of Doxepin considerably increased the step through latencies in the rats that received the doses of 1 and 5 mg/kg (P < 0.05). However, in the dose of 10 mg/kg, there wasn’t any significant change comparing to control group.Conclusion:These results indicate that Doxepin has desirable effects on cognitive functions in low doses. Therefore, Doxepin can be considered as memory enhancers that understanding the underling mechanisms need further investigation.

The Role of the Endocannabinoids in Suppression of the Hypothalamic-pituitary-adrenal Axis Activity by Doxepin.

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. Male Wistar rats received acute and four-week intraperitoneal injections of doxepin (3, 5, and 10 mg/kg) or its vehicle (0.9% saline). One hr after the last injection, animals were exposed to a 5 min swim stress session. In other cohorts of animals, the CB1 receptor antagonist AM251 (0.25, 0.5, and 1mg/kg) was injected 30 min before the administration of doxepin. Plasma corticosterone concentration was measured by enzyme-immunoassay at 45 min following stressing. 1, 5, and 12 hr after the last injection of doxepin, the contents of endocacannabinoids (anandamide and 2-arachidonylglycerol) within the lipid extracts of the prefrontal cortex, amygdala, hippocampus, and hypothalamus were determined using isotope-dilution liquid chromatography-mass spectrometry. Chronic treatment with doxepin (10 mg/kg) significantly reduced the secretion of corticosterone due to 5 min exposure to swim stress. Acute administration of doxepin evoked no effect. Pre-application of AM251 (1 mg/kg) abolished the ability of doxepin to reduce corticosterone secretion. Chronic administration of doxepin (10 mg/kg) led to a significant elevation of the endocannabinoids in the examined brain regions. It appears that doxepin exerts its effects, at least in part, through activation of the eCBs and the CB1 cannabinoid receptors play a major role in this regard.

Low-Dose Doxepin

Doxepin binds with high specificity and affinity to the histamine H(1) receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises H(1) receptors, which is believed to promote the initiation and maintenance of sleep. In three large, well designed, phase III trials in adult or elderly patients with chronic primary insomnia, oral, low-dose doxepin 3 or 6 mg once daily improved wake time after sleep onset, total sleep time and sleep efficiency to a significantly greater extent than placebo. Significant between-group differences in polysomnographic sleep recordings that favoured low-dose doxepin were evident after a single administration of the drug. Other efficacy measures, including patient-reported sleep quality, also favoured low-dose doxepin over placebo. Symptom control was maintained for up to 12 weeks of low-dose doxepin administration and there was no evidence of physical dependence or worsening insomnia after doxepin withdrawal. Oral, low-dose doxepin 6 mg was also significantly more effective than placebo in a large, well designed trial modelling transient insomnia in healthy adults, according to polysomnographic recordings (e.g. in latency to persistent sleep). Oral, low-dose doxepin was generally well tolerated in clinical trials.

Intrathecal administration of doxepin attenuated development of formalin-induced pain in rats

The aim of the present research was to assess the influence of a tricyclic antidepressant doxepin administered intrathecally (i.t.) on the pain behavior in the formalin test (100 microl of 12% formalin was injected into the dorsal part of the hind paw under halotane anesthesia) in male Wistar rats. The influence of doxepin (62.5 microg i.t.) on the pain threshold and number of formalin-induced pain behaviors, as well as antinociceptive effect of morphine was studied. Doxepin significantly increased the nociceptive threshold in the paw pressure test, reduced formalin-induced pain behavior and potentiated morphine antinociceptive effect in formalin test. The obtained results indicate that analgesic effect of doxepin used before the injury is observable at the spinal level after intrathecal treatment, but not only after peripheral administration, which was shown in our previous study. The results of the present research demonstrated a possibility to modify the spinal nociceptive process by administration of doxepin before the formalin injection.

Doxepin and ethanol interaction

The effect of short-term oral administration of doxepin, a tricyclic antidepressant, on voluntary drinking of ethanol was studied in the rat as a function of sex. The effects of doxepin on ethanol and acetaldehyde metabolizing enzymes of hepatic and selected endocrine tissues were made in the presence and in the absence of ethanol. A reduction in voluntary ethanol intake was determined after the initial doxepin dose. This effect was not apparent during continued drug administration. Subsequently, a statistically insignificant reduction of ethanol drinking was noted 24 h and 72 h post-drug termination. Hepatic alcohol and aldehyde dehydrogenase were not altered from respective controls by doxepin in the presence and absence of ethanol. Epididymal and testicular adlehyde dehydrogenase were inhibited by doxepin from control in rats maintained on ethanol or water, respectively. The results suggest lack of adverse effect of doxepin on peripheral metabolism of alcohol metabolizing enzymes as compared to adverse interaction with acetaldehyde metabolizing enzyme in the endocrine tissues studied.

Effects on opioid-induced rate reductions by doxepin and bupropion

Twelve pigeons key-pecked under a multiple variable interval 15-second, variable interval 150-second schedule of food reinforcement. Effects of two opioid drugs, buprenorphine and methadone, were determined alone and in combination with chronic daily administration of the antidepressants doxepin or bupropion. Methadone initially produced dose-dependent key-pecking rate reductions when administered acutely, prior to the session, while buprenorphine produced key-pecking rates that reached a plateau at 50–80% of baseline rate and were not reduced further by higher doses. Neither doxepin nor bupropion, given alone, had lasting effects on key-pecking rates. Chronic daily doxepin administration significantly attenuated methadone-induced response rate reductions. Bupropion reduced the effect of the highest methadone dose, but this effect was mitigated by the development of opioid tolerance. Unlike bupropion, doxepin interfered with the development of opioid tolerance. Neither antidepressant systematically altered effects of buprenorphine on key-pecking.

Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats

The present studies tested the hypothesis that histamine blockade stimulates appetite, while increases in histamine levels suppress appetite. Results show that the classical antihistamines cyproheptadine and promethazine both produced significant and long-lasting increases in food intake. Pronounced appetite stimulation was also seen following the administration of doxepin, the most potent antihistamine among the antidepressants. In contrast, administration of the histamine precursor histadine produced a profound suppression in food intake. The results thus suggest that an inverse relationship may exist between histamine and food intake.

Selected tricyclic antidepressants in the management of chronic benign pain.

Depression is often considered a symptom of intractable benign pain and is usually a situational or exogenous subtype. At our four hospital-based pain management centers we have evaluated and treated more than 5,000 patients for chronic pain. The treatment of more than 2,000 of these patients has included the administration of doxepin or amitriptyline. This article reviews the therapeutic use of selected tricyclic antidepressants in the treatment of chronic benign pain and depression, and emphasizes the blockage of serotonin reuptake as the mechanism of action. The benefits of doxepin and amitriptyline include sleep facilitation, low cardiotoxicity and incidence of anticholinergic effects, and anxiolytic properties.

Hot Flushes in a 76-Year-Old Man-Reply

In Reply.— Drs Harris and Schwartz are to be congratulated for finding so satisfying a solution to the problem of Dr Harris' patient. They are wise to emphasize that the resolution of the patient's symptoms after the administration of doxepin cannot be adduced as proof that the hot flushes were due to depression or a panic disorder. Objectively verifiable hot flushes, particularly those that awaken a patient at night, must be a quite unusual manifestation of a purely emotional disorder. Confessing openly my inbred and too often misguided reluctance to abandon a diagnosis as well as my vast ignorance of psychopharmacology, I suggest still that this patient's symptoms may result from a cerebral discharge that was controlled by an unpredicted action of a psychotropic drug. Nevertheless, the patient is doing well and I agree heartily that if it ain't broke, don't fix it. In response to Dr Kreider, hot flushes

Effect of lithium and rubidium on the ganglionic inhibitory action of norepinephrine

Close intraarterial infusion of lithium chloride (2 and 4 mEq/kg) transiently suppressed evoked postganglionic potentials in the superior cervical ganglion of the cat; lower doses (0.5 and 1 mEq/kg) had no effect on transmission. Potentiation of the ganglionic inhibitory effect of norepinephrine (NE) occurred at plasma concentrations of lithium equivalent to those found to be therapeutic in man. Concurrent administration of lithium (1 mEq/kg) and doxepin (25 mcg/kg) produced greater facilitation of the ganglionic suppressant effect of NE than either lithium or doxepin alone. Rubidium chloride (0.1, 0.5 and 1 mEq/kg) produced temporary blockade of ganglionic transmission; lower doses (0.05 and 0.075 mEq/kg) did not exhibit a ganglioplegic effect. Reduction of the ganglionic inhibitory activity of NE was observed at each dose level of rubidium. Administration of doxepin (25 mcg/kg) immediately after rubidium (0.075 mEq/kg) significantly reduced the inhibitory effect of the cation on NE activity. These results suggest that, in the cat superior cervical ganglion, lithium may block NE uptake and rubidium may promote NE release.

三環系化合物Doxepinの行動薬理学的研究

Doxepin, one of tricyclic antidepressants was examined as to whether or not it possesses a diazepam-like effect. Water-deprived rats were tested in an apparatus where they drank water under two kinds of conflict schedules. A clear diazepam-like effect was observed after long term administration of doxepin in the approach-withdrawal conflict schedule, although the potency was weaker than that of diazepam. In approach-avoidance conflict schedule a slight effect only was exhibited after doxepin. No marked sign was detected in the experiments after withdrawal of daily administration of doxepin.