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Objective To evaluate the effect of doxepin on the expression of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal cord of rats with neuropathic pain (NP).Methods Sixty clean-grade male Wistar rats in which intrathecal catheters were successfully implanted,weighing 200-250 g,were divided into 3 groups (n =20 each) by a random number table method:sham operation group (S group),NP group and doxepin group (D group).NP was induced by chronic constriction injury (CCI) to sciatic nerve.Doxepin 20 mmol/L (10 μl) was intrathecally injected at 3,7,14 and 21 days after CCI (T1-4) in group D.The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 1 day before CCI (T0) and at T1-4.The rats were sacrificed after measurement of pain threshold at T4,and L4-6 segments of the spinal cord were removed for determination of the expression of p38MAPK protein by Western blot.Results Compared with S group,MWT was significantly decreased and TWL was shortened at T2-4,and the expression of p38MAPK protein was up-regulated in NP and D groups (P＜0.05).Compared with NP group,MWT was significantly increased and TWL was prolonged at T2-4,and the expression of p38MAPK protein was down-regulated in D group (P＜0.05).Conclusion The mechanism by which doxepin mitigates NP is related to down-regulating p38MAPK expression in the spinal cord of rats.
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Objective: To observe the therapeutic efficacy of music electric stimulation of points in treating anxiety. Methods: 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. Results: 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<0.001), and the inter-group differences were statistically insignificant (P>0.05). Conclusion: 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.
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OBJECTIVES: We aimed to investigate the discontinuation rate and reasons of doxepin base prescription pattern in insomnia outpatients of psychiatry department of a university hospital. METHODS: 534 patients prescribed doxepin were screened. 201 patients were included and reviewed for their medical records retrospectively. The discontinuation rate and reasons of doxepin after 2 months of prescription were investigated. Patients were divided into three groups according to the prescription patterns. The initial group, prescribed doxepin as the first hypnotic, the add-on group, prescribed doxepin while maintaining existing hypnotics, and the switching group, prescribed doxepin after discontinuation of existing hypnotics. RESULTS: The discontinuation rate after 2 months of prescription of doxepin was 56.2%. There were significant differences in the discontinuation rate among three groups. The initial group had the highest while the add-on group had the lowest (p=0.018). In reasons for discontinuation of doxepin among three groups, lack of efficacy (p < 0.001) and adverse events (p < 0.001) were significantly higher in the add-on group. In the initial group, patient's refusal (p=0.022) and unknown or loss to follow up (p < 0.001) were significantly higher. CONCLUSIONS: The results of this study suggested that add-on is superior than switching method and gradual reduction of existing hypnotics is necessary to maintain doxepin treatment and prevent adverse events. Additional large scale prospective studies are needed to evaluate various factors and risks of discontinuation of doxepin.
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Humans , Doxepin , Follow-Up Studies , Hypnotics and Sedatives , Medical Records , Methods , Outpatients , Prescriptions , Prospective Studies , Retrospective Studies , Sleep Initiation and Maintenance DisordersABSTRACT
A selective, sensitive and rugged liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay has been developed for the simultaneous determination of doxepin (Dox) and its pharmacologically active metabolite, nordoxepin (NDox) in human plasma. The analytes and their internal standards (IS) were extracted from 500 μL of human plasma by liquid-liquid extraction using methyl tert-butyl ether. Chromatographic separation was achieved on Hypurity C8 column (100 mm × 4.6 mm, 5 μm) using a mixture of acetonitrile-methanol (95:5, v/v) and 2.0 mM ammonium formate in 93:7 (v/v) ratio. Detection was accomplished by tandem mass spectrometry in the positive ionization and multiple reaction monitoring acquisition mode. The protonated precursor to product ion transitions studied for Dox, NDox, and their corresponding ISs, propranolol and desipramine, were m/z 280.1-107.0, 266.0 -107.0, 260.1-116.1 and 267.1-72.1, respectively. A linear dynamic range of 15.0–3900 pg/mL for Dox and 5.00– 1300 pg/mL for NDox was established with mean correlation coefficient (r2) of 0.9991 and 0.9993, respectively. The extraction recovery ranged from 86.6％–90.4％ and 88.0％–99.1％ for Dox and NDox, respectively. The intra-batch and inter-batch precision (％ CV) across quality control levels was ≤ 8.3％ for both the analytes. Stability evaluated under different storage conditions showed no evidence of degradation and the ％ change in stability samples compared to nominal concentration ranged from 4.7％ to 12.3％. The method was successfully applied to a bioequivalence study of 6 mg doxepin hydrochloride orally disintegrating tablet in 41 healthy Indian subjects under fasting and fed conditions.
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Objective To investigate the effect of small dose of doxepin combined with psychological behav-ior intervention in the treatment of insomnia.Methods 21 patients with insomnia were selected as the study sub-jects,took doxepin 25mg before going to bed at every night,to the research object and psychological behavior interven-tion by hand,continuous treatment for 8 weeks.Used the method of questionnaire survey before and after two periods of time,assessed by using pittsburgh Sleep Quality mder(PSQI)scale,analysed the correlation between sleep quality and sleep beliefs attitudes.Results After treatment with 8 weeks,subjected sleep quality,sleep difficulties,sleep time,sleep efficiency,sleep disturbance,hypnotic drug use,and daytime functional scores were lower than before treat-ment (t =17.34,16.65,10.54,13.37,11.65,7.66,11.57,all P <0.05 ),the difference of the score of PSQI between after treatment[(5.80 ±0.97)points]and before treatment[(13.34 ±2.28)points]was significant(t =21.27,P <0.01).Conclusion Small dose of doxipin combined with psychological behavior intervention in treating insomnia can improve the sleep quality of patients.
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Objective To investigate the effect of caspases-3 on doxepin-induced apoptosis in rat neurons.Methods The PC12 cells seeded in culture plates were randomly divided into 4 groups (n =10 each) using a random number table:normal control group (group C);doxepin group (group D);caspase-3 inhibitor Z-DEVD-FMK group (group Z);doxepin + Z-DEVD-FMK group (group DZ).In group C,the cells were continuously incubated for 24 h.In group D,doxepin was added with the final concentration of 120 μmol/L,and the cells were continuously incubated for 24 h.In group Z,Z-DEVD-FMK was added with the final concentration of 10 μmol/L,and the cells were continuously incubated for 24 h.In group DZ,doxepin and Z-DEVD-FMK with the final concentrations of 120 and 10 μmol/L,respectively,were added,and the cells were continuously incubated for 24 h.After 24 h of incubation,the cell viability was detected by methyl thiazolyl tetrazolium assay,the cell morphology was observed under inverted microscope,and the neuronal apoptosis was measured by flow cytometry.Apoptosis rate was calculated.Results Compared with group C,the cell viability was significantly decreased,and apoptosis rate was increased in D and DZ groups (P＜0.01),and no significant change was found in the parameters mentioned above in group Z (P ＞ 0.05).Compared with group D,the cell viability was significantly increased,and apoptosis rate was decreased in group DZ (P＜ 0.01).The morphological changes were significantly mitigated in group DZ as compared with group D.Conclusion Caspases-3 may mediate doxepin-induced apoptosis in rat neurons.
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Objective To investigate the role of mitochondrial apoptotic pathway in intrathecal doxepin?induced apoptosis in rat neurons. Methods Twenty?four adult male Wistar rats, weighing 250-300 g, in which intrathecal catheters were successfully implanted without complications, were randomly divided into 4 groups ( n=6 each) using a random number table: control group ( group C) and different concentrations of doxepin groups (D5, D10 and D20 groups). In D5, D10 and D20 groups, 5, 10, and 20 mmol∕L doxepin 0. 2 μl∕g were injected intrathecally, respectively. In group C, the equal volume of normal saline was given instead. At 6 h after intrathecal administration, the animals were sacrificed, and the lumbar segments of the spinal cords were obtained for detection of the cell apoptosis ( by TUNEL assay) , expression of Bax and Bcl?2 ( by immunohistochemistry) , release of cytochrome c ( Cyt c) , and expression of caspase?3, caspase?8 and caspase?9 mRNA ( using real?time reverse transcriptase polymerase chain reaction) . Apoptosis rate and Bcl?2∕Bax ratio were calculated. Results Compared with group C, the expression of Bax was significantly up?regulated, the expression of Bcl?2 was down?regulated, Bcl?2∕Bax ratio was decreased, the release of Cyt c and apoptosis rate were increased, and the expression of caspase?3 and caspase?9 mRNA was up?regulated in D10 and D20 groups, the expression of Bcl?2 was down?regulated in group D20 ( P0.05). The expression of Bax was significantly up?regulated, Bcl?2∕Bax ratio was decreased, the release of Cyt c and apoptosis rate were increased, and the expression of caspase?3 and caspase?9 mRNA was up?regulated in D10 and D20 groups, and the expression of Bcl?2 was down?regulated in group D20 as compared with group D5 ( P0.05) . Conclusion Mitochondrial apoptotic pathways, but not death receptor pathway, is involved in intrathecal doxepin?induced apoptosis in rat neurons.
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Objective To investigate the neurotoxicity of intrathecal (IT) doxepin in rats.Methods Twenty-four adult male Wistar rats weighing 250-300 g in which intrathecal micro-catheter was successfully implanted without complications were randomly divided into 4 groups ( n =6 each):control group ( group N ) and 3 doxepin groups receiving IT doxepin 40,20 and 10 mmol/L 0.2 μl/g respectively (groups D40,D20,D10 ).In N group normal saline was injected IT instead of doxepin.The animals were killed at 6 h after IT administration.The lumbar segment of the spinal cord was removed for microscopic examination and determination of myelin basic protein (MBP) content in the spinal cord using a double-antibody sandwich (ELISA).Results The severity of neuronal damage and decrease in MBP content in the spinal cord induced by IT doxepin were dose-dependent.Conclusion The neurotoxicity induced by IT doxepin is dose-dependent.
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Objective To observe the effect of doxepin hydrochloride on refractory hiccups after stroke.Methods 60 patients with refractory hiccup of post-stroke were randomly divided into 2 groups, treatment group :30 cases were given doxepin tablets 25～50 mg orally,3 times a day for 2～8 days;the control group :30 patients were orally adaine stened alprazolam 0. 4mg,3 times a day for 2～8 days. Results The total effective rate was 96. 67% in the treatment group,the total effective rate was 56. 67% in the control group,the effect of the treatment group is better than the control group( P＜0. 05 ). Conclusion The effect of doxepin hydrochloride on refractory hiccups after stroke is obvious,the method is simple,takes effect quickly,no significant side effects,the price is low.
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193 patients with irritable bowel syndrome (IBS) were divided into 3 groups stochastically:73 cases were treated with both trimebutine malate and doxepin. 56 cases were only treated with doxepin, and this group was given doxepin to take orally. The other 64 cases were only treated with trimebutine malate. This group were given trimebutine malate to take orally. Doxepin was given 12.5-25.0 mg tid po, and trimebutine malate was given 200 mg tid po. This is for a course of 4-week-therapy. The rates of the total response of the 3 groups were 95.9%, 83.9% and 81.3% respaefively. The effect of the combination of the 2 drugs is much higher than the other two (P<0.01), and especially it has the highest effect on diarrhea type IBS. The rates of the improvement of nervos and mental symptoms were 87.0%, 79.0% and 71.6% respectively. The effect of combination use is the highest. It suggests that both the single use and combination use of doxepin and trimebutine malate has the effect on the treatment of IBS, but the combination use can improve the effect obviously.
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Objective To study the effect of doxepin on some gut hormones of psychological stress ratsMethods To stimulate the 6-OHDA.treated rats to attack the experimental rats as social psychological stressor,and to detect the change of levels of plasma motilin(MTL) and vasoactive intestinal peptide(VIP) of experimental rats.Results The level of plasma MTL and VIP of the rats in model group were (318.5±89.37)pg/ml and(65.78±12.10)pg/ml.There were significant difference(P<0.01)between model group and normal group [(223.43+73.05)mg,/mol,(88.27±16.90)me/mol].The level of plasma MTL and VIP of the rats in control group were(267.37±80.33)pg/ml and(77.54±13.36)pg/ml.There were significant difference(P<0.05)between control group and model group. Conclusion Strong psychological stress could influence levels of plasma MTL and VIP of the rats.But Doxepin could adjust the emotional state of psychological stress rats and relieve the effect of psychological stress on levels of plasma MTL and VIP of rats,thus affect gastrointestinal motility.
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OBJECTIVE:To establish a rapid and sensitive HPLC method for simultaneous determination of plasma concentrations of 6 antidepressants.METHODS:With diprozin as internal standard,the alkalized samples were extracted by liquid-liquid extraction and separated on a Phenomenex-C18 column using acetonitrile-0.05 mol?L-1 sodium dihydrogen phosphate(pH was adjusted to 2.5 by phosphoric acid) as mobile phase at a flow rate of 1.2 mL?min-1 by a gradient elution.The column temperature was set at 40℃.Venlafaxine was detected by fluorescence detection at an Ex wavelength of 276 nm and Em wavelength of 598 nm;doxepin,paroxetine,sertraline,fluoxetine and amitriptyline were detected at an UV detection wavelength of 200 nm.RESULTS:The linear ranges of venlafaxine,doxepin,paroxetine,sertraline,fluoxetine and amitriptyline were 5～1 000 ?g?L-1,40 ～200 ?g?L-1,20～800 ?g?L-1,40～1 000 ?g?L-1 and 10～400 ?g?L-1,respectively,with correlation coefficients ≥0.990 for all.Both the intra-day RSD and inter-day RSD were less than 15%;the extraction recovery rates were greater than 60% and methodological recovery were greater than 90% for all the samples.CONCLUSION:The method is simple,economical,rapid,accurate and sensitive,and it is applicable for the clinical monitoring of plasma drug concentrations as well as the analysis and pharmacokinetic study of toxic drugs.
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BACKGROUND: Eczematous dermatitis is associated with severe pruritus, but there are only a few effective treatment modalities. Preliminary studies suggest that topical application of doxepin cream is effective in the treatment of eczematous dermatitis. OBJECTIVE: This study was undertaken to evaluate the efficacy and safety of topical 5% doxepin cream in reducing ruritus associated with eczematous dermatitis in Korea. METHODS: A total of 62 patients with eczematous dermatitis, who daily experienced severe pruritus for at least 1 week, were enrolled in the study. Five percent doxepin cream was applied twice a day on the baseline visit, and four times daily for up to 7 days. We evaluated pruritus scores using visual analog scales, which consisted of a 100-mm horizontal line labeled "no itch" and "worst itch imaginable" at opposite ends. RESULTS: Pruritus scores evaluated by patients revealed significantly-better improvement on each visit day. Furthermore, there was a significant decrease in the pruritus scores and erythema evaluated by physicians on each visit day. Furthermore, the most common adverse effects were a stinging sensation and aggravation of erythema at the site of application. CONCLUSION: Five percent doxepin cream is safe and effective in reducing pruritus in patients with eczematous dermatitis.
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Humans , Bites and Stings , Doxepin , Eczema , Erythema , Korea , Pruritus , Sensation , Visual Analog ScaleABSTRACT
BACKGROUND: Atopic dermatitis is associated with severe pruritus for which effective topical treatment is lacking. As a potent H1 and H2 antagonist, the antipruritic effect of topical doxepin has been demonstrated in eczematous dermatitis. OBJECTIVE: We evaluated the efficacy and safety of topical 5% doxepin cream in relieving pruritus associated with atopic dermatitis. METHODS: A total of 44 patients with atopic dermatitis, who had moderate to severe daily pruritus for at least 1 week, were enrolled in the double-blind, vehicle-controlled study. Randomly assigned 5% doxepin cream or vehicle cream was applied four times daily for 7 days trial. RESULTS: Relief of pruritus was achieved in 85% of doxepin-treated patients and 57% of vehicle-treated patients by day 7. At each study visit, the physician's global evaluation for relief of pruritus showed significant improvement in the doxepin treatment group (p < 0.01). Visual analogue scales for pruritus severity and pruritus relief showed similar improvements in the doxepin-treated group. The most common adverse effects reported included localized erythema, xerosis (doxepin group, n=5; vehicle group, n=3) and drowsiness (doxepin group, n=2; vehicle group, n=0). CONCLUSION: Topical doxepin is effective in reducing pruritus in patients with atopic dermatitis. It has apparently a short-term low risk of major side effects or sensitization.
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Humans , Dermatitis, Atopic , Doxepin , Eczema , Erythema , Pruritus , Sleep Stages , Weights and MeasuresABSTRACT
Doxepin hydrochloride cream with potent H1 and H2 blocker activity is a tricyclic antidepressant, which is structurally similar to phenothiazines, and also known to be a contact sensitizer and photosensitizer. We report a case of allergic contact dermatitis due to doxepin hydrochloride cream in a 75-year-old-man, who developed facial edema and eczema at the application sites (face, neck and upper trunk) within several hours of application of doxepin hydrochloride cream. Clinicians should be aware of the possibility of allergic contact dermatitis to doxepin cream, if the condition worsens with use of this medication.
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Dermatitis, Allergic Contact , Dermatitis, Contact , Doxepin , Eczema , Edema , Neck , PhenothiazinesABSTRACT
OBJECTIVE:To evaluate the efficacy and adverse effects of paroxetine alone or in combination with small dose of doxepin for somatization disorder.METHODS:280 patients with somatization disorder were randomly assigned to receive paroxetine alone or in combination with small dose of doxepin for 8 weeks.Clinical global impression scale(CGI)and symptom check list(SCL-90)were used to assess the efficacy,and treatment emergent symptom scale(TESS)was used to assess the adverse effects.RESULTS:After treatment for 8 weeks,CGI score showed the total effective rate was 87.5% in the patients treated with paroxetine alone versus 93.8% in those treated with paroxetine in combination with small dose of doxepin(P0.05).CONCLUSION:Paroxetine in combination with small dose doxepin showed better efficacy for somatization disorder yet without increasing adverse effects as compared with paroxetine alone.
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Aim To study the anti-itching and anti-hypersensitivity effects of Doxepin hydrochloride cream. Methods The effects of Doxepin hydrochloride cream on the pruritus of skin in mice due to 4-AP and guineapigs due to histamine phosphate were observed. The inhibitory actions of it on the increase of abdominal cavity capillary permeability in mice due to acetic acid and the angiectasis of skin in rats due to histamine were also observed. Its effects on the delayed-type hypersensitivity (DTH) of mice due to 2, 4-dinitrochlorobenzol (DNCB) and the homologous passive anaphylaxis of skin in rats were used to investigate its anti-hypersensitivity actions. Results The application of Doxepin hydrochloride cream (50, 125, 250 mg?kg -1) on the skin of mice had significant inhibitory actions on the pruritus of skin caused by 4-AP, and the application of Doxepin hydrochloride cream (10, 25, 50 mg?kg -1) on the skin of guinea pigs also had significant inhibitory actions on the pruritus of skin caused by histamine phosphate. The application of Doxepin hydrochloride cream (10,25,50 mg?kg -1 and 50,125,250 mg?kg -1) on skin inhibited the increase of skin capillary permeability in rats caused by histamine phosphate and the increase of abdominal cavity capillary permeability in mice caused by acetic acid. The application of Doxepin hydrochloride cream (50, 125, 250 mg?kg -1 and 10, 25, 50 mg?kg -1) on skin also significantly inhibited the delayed-type hypersensitivity in mice due to 2, 4-dinitrochlorobenzol and the homogeneous cutaneous anaphylaxis in rats. Conclusions Doxepin hydrochloride cream can relieve itching,inhibit the increase of capillary permeability caused by inflammatory substances. It also has significant inhibitory actions on TypeⅠ and Type Ⅳ allergic reactions.
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AIM To observe protective effects of doxepin on focal cerebral ischemia-reperfusion(I-R)injured rats. METHODS 120 rats were randomly divided into ischemia-reperfusion group,doxepin, nimodipine group and sham-operated group respectively, ischemia-reperfusion model was made by using the suture emboli method, the content of NO and MDA, activities of NOS and SOD in the cerebral tissues and the intracellular [Ca 2+ ] i in the cerebral cortex were determined respectively. RESULTS The content of NO, MDA and [Ca 2+ ] i and the activities of NOS decreased and the activities of SOD increased significantly in the doxepin and nimodipine group compared with ischemia-reperfusion group respectively(P
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OBJECTIVE:To compare the percutaneous absorbency between imported and domestic5%doxepin cream.METHODS:In a cross design,8health male volunteers were enrolled in the study.Determination was performed by HPLC with chlorimipramine as internal standard.RESULTS:The same dose of domestic and imported doxepin cream was topically applied to the forearm skin of the volunteers for8consecutive days.The blood drug levels were very low in both groups without significant difference.CONCLUSION:The percutaneous absorbency of domestic5%doxepin cream can reach that of imported ones and the domestic cream is safe and effective.
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OBJECTIVE:To study the preparation and quality control of compound doxepin hydrochloride cream.METHO DS:The compound cream was prepared with doxepin hydrochloride and triamcinolone acetonide,and the contents were determinated by UV-spectrophotometry and HPLC respectively.RESULTS:The calibration curves were linear in the range of the concentrations of the experiment respectively,r=0.9999.CONCLUSION:The method is simple,accurate and suitable for the quality control of this preparation.