同: Tofranil
関: Imipramine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/03/01 16:17:02」(JST)

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Imipramine (G 22355), sold as Tofranil and also known as melipramine, is a tricyclic antidepressant (TCA) of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).

It has also been evaluated for use in panic disorder.^[3]

Therapeutic uses

Imipramine is used in the treatment of depression, such as depression associated with agitation or anxiety. It is similar in efficacy to the antidepressant drug moclobemide.^[4] It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions.

History

In the late 1950s, imipramine was the first tricyclic antidepressant to be developed (by Ciba). At the first international congress of neuro-pharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as "depressive psychosis". The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved insufficient. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression.^[5] It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania.^[6] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.

Before the advent of SSRIs, its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released tricyclics. Today it is no longer used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.

Mechanism of action

Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, ADHD, enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.

The mechanisms of imipramine's medicinal action include, but are not limited to, effects on:

Serotonin (5-HT): very strong reuptake inhibition. Imipramine has the second highest attraction for the serotonin transporter (SERT) in the tricyclic antidepressant class behind clomipramine. This provides a very strong and proportional effect on the blockade of serotonin reuptake. Moderating this effect, however, is imipramine's continual conversion in the body to its metabolite desipramine, which has extremely strong and relatively selective noradrenergic effects. This blend of imipramine and desipramine circulating together within the body provides a powerful one-two punch in simultaneously blockading both serotonin and norepinephrine reuptake.
Norepinephrine (NE): strong reuptake inhibition.
Dopamine (DA): reuptake and release at D₁ and D₂ receptors. Similar but less potent than psychostimulants, dopamine agonists, and the atypical antidepressant bupropion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SER and ACh, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with imipramine. Enhancement of brain dopamine activity has been implicated in imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it has only 5% of the potency of amitriptyline or paroxetine, see the table below).^{[citation needed]}
Acetylcholine (ACh): imipramine is an anticholinergic. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population. Imipramine is an antagonist at M₂ muscarinic acetylcholine receptors (see external links). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of imipramine as well. The antimuscarinic effect is also responsible for rapid heart rate (tachycardia).
Epinephrine: imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).
σ Receptor and enkephalinase: Activity on σ-receptors is present, but it is very low (Ki of 520 nM on σ-receptors, see references) and it is about half the power of amitryptiline (300 nM).
Histamine: imipramine is an antagonist at histamine H₁ receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imipramine is sometimes prescribed as a sleep aid in low doses.
BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promotor, and also reduced expression of hippocampal HDAC5.^[7]^[8]
μ Receptor: imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.^[9]

Comparison with other antidepressants

Binding Profile of popular TCAs towards their cloned human (unless otherwise specified) molecular targets (K_i in nM)^[10]^[11]

Drug	SERT	NET	DAT	α₁	α_2A	D₂	H₁	M₁	M₃	5-HT_1A	5-HT_2A	5-HT_2C	5-HT₆	5-HT₇
imipramine	10.4	51.7	8,500	-	3,100 (Human, Brain)	726	11.0	42	60	>10,000	120 (Rat, Cloned)	120 (Rat, Cloned)	190 (Rat, Cloned)	1,000 (Rat, Cloned)
desipramine	179	2.27	>10,000	130	1,380 (Human, Brain)	1,560	45.6	110	210	>10,000	114 (Rat, Cloned)	496 (Rat, Cloned)	-	1,000 (Rat, Cloned)
amitriptyline	3.13	22.4	4,440	24 (Human, Brain)	690 (Human, Brain)	1,460 (Human, Brain)	0.5	14.7	12.8	450 (Human, Brain)	5.60 (Rat, Cortex)	6.15 (Rat, Cloned)	103	114 (Rat, Cloned)
clomipramine	0.21	45.9	2,610	3.2	525	120	31.2	-	-	>10,000	35.5	64.6	53.8 (Rat, Cloned)	127 (Rat, Cloned)

Metabolism

Within the body, imipramine is converted to desipramine, another TCA.

Side effects

Those listed in Italic text below denote common side effects.^[12]

Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia
Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias
Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis
Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change
Genitourinary: urinary retention
Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia
Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity

References

^ "Bioavailability of imipramine tablets relative to a stable isotope-labelled internal standard: increasing the power of bioavailability tests". Journal of Pharmacokinetics and Biopharmaceutics 7 (3): 233–248. June 1979. doi:10.1007/bf01060015. PMID 480146.
^ ^a ^b ^c ^d "PRODUCT INFORMATION TOLERADE® (imipramine hydrochloride)". TGA eBusiness Services. PMIP Pty Ltd. 4 June 2013. Retrieved 16 October 2013.
^ Lepola, U; Arató, M; Zhu, Y; Austin, C (June 2003). "Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder" (PDF). The Journal of Clinical Psychiatry 64 (6): 654–62. doi:10.4088/JCP.v64n0606. PMID 12823079.
^ Delini-Stula, A; Mikkelsen, H; Angst, J (October 1995). "Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies". Journal of Affective Disorders 35 (1–2): 21–30. doi:10.1016/0165-0327(95)00034-K. PMID 8557884.
^ Healy, David: The Antidepressant Era, page 211. Harvard University Press, 1997.
^ Bottlender, R; Rudolf, D; Strauss, A; Möller, H. J. (1998). "Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression". European Archives of Psychiatry and Clinical Neuroscience 248 (6): 296–300. doi:10.1007/s004060050053. PMID 9928908.
^ Tsankova, N. M.; Berton, O; Renthal, W; Kumar, A; Neve, R. L.; Nestler, E. J. (April 2006). "Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action". Nature Neuroscience 9 (4): 519–25. doi:10.1038/nn1659. PMID 16501568.
^ Krishnan, V; Nestler, E. J. (October 2008). "The molecular neurobiology of depression". Nature 455 (7215): 894–902. Bibcode:2008Natur.455..894K. doi:10.1038/nature07455. PMC 2721780. PMID 18923511.
^ De Gandarias, J. M.; Echevarria, E; Acebes, I; Silio, M; Casis, L (July 1998). "Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain". Arzneimittel-Forschung 48 (7): 717–9. PMID 9706370.
^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 28]. Chapel Hill (NC): University of North Carolina. 1998–2013. Available from: http://pdsp.med.unc.edu/pdsp.php
^ Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
^ Skidmore-Roth, L. (ed.). (2010). Mosby's Nursing Drug Reference (23rd ed.). St. Louis, MO: Mosby Elsevier.

External links

Imipramine – Medicinenet.com
Neurotransmitter – Neurotransmitter.net
Imipramine bound to proteins in the PDB

UpToDate Contents

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1. 急性ストレス障害の治療 treatment of acute stress disorder
2. 成人における双極性障害：抗うつ剤による大うつ病エピソードの治療 bipolar disorder in adults treating major depression with antidepressants
3. 成人における単極性うつ病と三環系抗うつ剤および四環系抗うつ剤：薬理学、投与、
および副作用 unipolar depression in adults and tricyclic and tetracyclic drugs pharmacology administration and side effects
4. 尿失禁の治療 treatment of urinary incontinence
5. 急性ストレス障害：疫学、臨床症状、および診断 acute stress disorder epidemiology clinical manifestations and diagnosis

English Journal

LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders.

Rorick-Kehn LM1, Witkin JM2, Statnick MA2, Eberle EL2, McKinzie JH2, Kahl SD2, Forster BM2, Wong CJ2, Li X2, Crile RS2, Shaw DB2, Sahr AE2, Adams BL2, Quimby SJ2, Diaz N2, Jimenez A2, Pedregal C2, Mitch CH2, Knopp KL2, Anderson WH2, Cramer JW2, McKinzie DL2.Author information 1Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. Electronic address: rorickkehnlm@lilly.com.2Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.AbstractKappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (tmax: 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED50 = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders.
Neuropharmacology.Neuropharmacology.2014 Feb;77:131-44. doi: 10.1016/j.neuropharm.2013.09.021. Epub 2013 Sep 23.
Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be benefi
PMID 24071566

Additive antidepressant-like effects of fasting with imipramine via modulation of 5-HT2 receptors in the mice.

Li B, Zhao J, Lv J, Tang F, Liu L, Sun Z, Wang L, Siwela SP, Wang Y, Song Y, Manchishi SM, Cui R.Author information National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China; Jilin Key Laboratory of Animal Resource Conservation and Utilization, Northeast Normal University, Changchun 130024, China.AbstractRecently, studies show that intermittent fasting and caloric restriction may improve symptoms of depression. However, there is little scientific evidence regarding the literature on the antidepressant-like effects of acute fasting. The present study aims to investigate the antidepressant-like effects and its influence on brain levels of the transcription factor cAMP response element-binding protein (CREB) and its phosphorylated form (p-CREB) in different time periods of fasting mice. Furthermore, the additive antidepressant-like effects of fasting with imipramine and the possible involvement of the 5-HT2 receptors were examined. In the present study 9h, but not 3h and 18h of fasting significantly reduced immobility time in the forced swimming test (FST) without alteration in locomotor activity in the open field test. 9h fasting also enhanced the ratio of p-CREB/CREB in the frontal cortex and hippocampus. Co-administration of 9h of fasting and imipramine (30mg/kg, i.p) produced the additive antidepressant-like effects in the FST and increased the ratio of p-CREB/CREB. Meanwhile, the additive effects were partially reversed by treatment with a 5-HT2A/2C receptor agonist, (±)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) (5mg/kg, s.c). Furthermore, the antidepressant-like effects of 9h fasting was also blocked by DOI compared to the non-fasting control group. Serum corticosterone level, but not 5-HT and noradrenaline, was significantly increased in a time-dependent manner following different time periods of fasting. Taken together, these results suggest that acute fasting produces antidepressant-like effects via enhancement of the p-CREB/CREB ratio, and additive antidepressant-like effects of fasting with imipramine may be related to modulating 5-HT2 receptors.
Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2014 Jan 3;48:199-206. doi: 10.1016/j.pnpbp.2013.08.015. Epub 2013 Sep 12.
Recently, studies show that intermittent fasting and caloric restriction may improve symptoms of depression. However, there is little scientific evidence regarding the literature on the antidepressant-like effects of acute fasting. The present study aims to investigate the antidepressant-like effect
PMID 24036107

Increased oxidative stress in prefrontal cortex and hippocampus is related to depressive-like behavior in streptozotocin-diabetic rats.

de Morais H, de Souza CP, da Silva LM, Ferreira DM, Werner MF, Andreatini R, da Cunha JM, Zanoveli JM.Author information Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H dos Santos S/N, P.O. Box 19031, Curitiba-PR 81540-990, Brazil.AbstractDepression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of prolonged treatment with insulin (INS), the antioxidant vitamin E (VIT E) or the antidepressant imipramine (IMI) was evaluated in animals submitted to forced swimming test. Oxidative stress parameters (lipid peroxidation product levels, reduced gluthatione levels and catalase and superoxide dismutase activities) were also evaluated in brain areas related to depression, prefrontal cortex (PFC) and hippocampus (HIP). Our data show that treatment of streptozotocin-induced diabetic (DBT) rats with INS (6UI/day, s.c.) prevented the blood glucose increase, reduced the immobility time, an antidepressant-like behavior, and normalized the reduced weight gain. Although the VIT E treatment (300mg/kg, p.o.) had not altered the blood glucose levels, this treatment was able to reduce the immobility time and to reestablish the reduced weight gain in DBT rats. Differently, treatment with IMI (15mg/kg, i.p.) induced antidepressant-like behavior in normoglycemic besides DBT animals. While VIT E and IMI treatments restored only specific oxidative stress parameters, INS was able to prevent all changed parameters evaluated in both PFC and HIP from DBT animals. Therefore, our data provide further evidence of the importance of oxidative stress in PFC and HIP in the pathophysiology of depression related to diabetes.
Behavioural brain research.Behav Brain Res.2014 Jan 1;258:52-64. doi: 10.1016/j.bbr.2013.10.011. Epub 2013 Oct 16.
Depression is a common comorbid in diabetic patients. The pathophysiologic mechanisms that relate this comorbidity is not completely elucidated yet, although several lines of evidence point out that increased oxidative stress resulting from hyperglycemia may have a crucial role. Thus, the effect of
PMID 24140504

Japanese Journal

Extra-Weak Chemiluminescence of Drugs. V. The Extra-Weak Chemiluminescence of Imipramine Hydrochloride Produced by Autoxidation(Pharmaceutical)

佐藤秀昭,江戸清人,水柿道直
Chemical & pharmaceutical bulletin 34(12), 5110-5114, 1986-12-25
The chemiluminescence (CL) produced by autoxidation of imipramine hydrochloride was investigated. The CL generated from imipramine hydrochloride was strongly enhanced by replacing nitrogen with either …
NAID 110006280845

光眼輪筋反射の late component の発現機序に関する実験的研究

服部裕子
The Journal of Kansai Medical University 34(2), 377-426, 1982
… Barbiturate, chlorpromazine, diazepam and tofranil had inhibitory effect predominantly on all the components of PPR. … ERG was not affected significantly with the administration of such chemicals as barbiturate, chlorpromazine, diazepam, tofranil, cardiazol, amphetamine and CDP-choline.<BR>14. …
NAID 130004625530

末期癌患者の頑痛に対するTofranilの鎮痛効果

西村敏雄 [他]
産科と婦人科 38(2), 196-202, 1971-02
NAID 40017817362

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関連記事	「Tofranil」

「Tofranil」

Imipramine
Systematic (IUPAC) name
	3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
Clinical data
Trade names	Tofranil
AHFS/Drugs.com	monograph
MedlinePlus	a682389
Pregnancy; category	AU: C; US: N (Not classified yet); ;
Routes of; administration	Oral
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only); US: ℞-only;
Pharmacokinetic data
Bioavailability	94-96%
Protein binding	86%
Metabolism	Hepatic (CYP1A2, CYP2C19, CYP2D6); Main active metabolite desipramine
Biological half-life	20 hours
Excretion	Renal (80%), Faecal (20%) (mostly as inactive metabolites)
Identifiers
CAS Number	50-49-7
ATC code	N06AA02
PubChem	CID 3696
IUPHAR/BPS	357
DrugBank	DB00458
ChemSpider	3568
UNII	OGG85SX4E4
KEGG	D08070
ChEBI	CHEBI:47499
ChEMBL	CHEMBL11
Chemical data
Formula	C19H24N2
Molar mass	280.407 g/mol
	SMILES c1cc3c(cc1)CCc2c(cccc2)N3CCCN(C)C ;
	InChI InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3 ; Key:BCGWQEUPMDMJNV-UHFFFAOYSA-N ;
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トフラニール

関: imipramine、imipramine hydrochloride

[Pharm-1] "Bioavailability of imipramine tablets relative to a stable isotope-labelled internal standard: increasing the power of bioavailability tests". Journal of Pharmacokinetics and Biopharmaceutics 7 (3): 233–248. June 1979. doi:10.1007/bf01060015. PMID 480146.

[TOLERADE-2] "PRODUCT INFORMATION TOLERADE® (imipramine hydrochloride)". TGA eBusiness Services. PMIP Pty Ltd. 4 June 2013. Retrieved 16 October 2013.

[pmid12823079-3] Lepola, U; Arató, M; Zhu, Y; Austin, C (June 2003). "Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder" (PDF). The Journal of Clinical Psychiatry 64 (6): 654–62. doi:10.4088/JCP.v64n0606. PMID 12823079.

[pmid8557884-4] Delini-Stula, A; Mikkelsen, H; Angst, J (October 1995). "Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies". Journal of Affective Disorders 35 (1–2): 21–30. doi:10.1016/0165-0327(95)00034-K. PMID 8557884.

[5] Healy, David: The Antidepressant Era, page 211. Harvard University Press, 1997.

[urlSpringerLink_.E2.80.93_Journal_Article-6] Bottlender, R; Rudolf, D; Strauss, A; Möller, H. J. (1998). "Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression". European Archives of Psychiatry and Clinical Neuroscience 248 (6): 296–300. doi:10.1007/s004060050053. PMID 9928908.

[7] Tsankova, N. M.; Berton, O; Renthal, W; Kumar, A; Neve, R. L.; Nestler, E. J. (April 2006). "Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action". Nature Neuroscience 9 (4): 519–25. doi:10.1038/nn1659. PMID 16501568.

[8] Krishnan, V; Nestler, E. J. (October 2008). "The molecular neurobiology of depression". Nature 455 (7215): 894–902. Bibcode:2008Natur.455..894K. doi:10.1038/nature07455. PMC 2721780. PMID 18923511.

[pmid9706370-9] De Gandarias, J. M.; Echevarria, E; Acebes, I; Silio, M; Casis, L (July 1998). "Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain". Arzneimittel-Forschung 48 (7): 717–9. PMID 9706370.

[10] National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 28]. Chapel Hill (NC): University of North Carolina. 1998–2013. Available from: http://pdsp.med.unc.edu/pdsp.php

[11] Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.

[12] Skidmore-Roth, L. (ed.). (2010). Mosby's Nursing Drug Reference (23rd ed.). St. Louis, MO: Mosby Elsevier.

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