Rats' tolerance to morphine-induced analgesia is decreased by zimelidine (15 mg/kg, IP once) [3]. For 14 days, zimelidine (5 mg/kg, IP) does not change the way CA3 hippocampal pyramidal neurons respond to 5-HT microiontophoresis [2]. In rats who have been starved, zimelidine (0.2, 2 and 20 nmol/100 nL) in the medial amygdala (MeA) causes dose-dependent anorexigenic behaviors [4].

Animal/Disease Models: Male Wistar albino rats (160-180 g, n=72) [3]
Doses: 15 mg/kg
Route of Administration: IP, once
Experimental Results:Dramatically attenuated the development and expression of morphine tolerance. Through the tail flick and hot plate tests, the maximum analgesic effect of zimelidine was obtained at the 60-minute measurement in the zimelidine group and at the 30-minute measurement in the morphine-tolerant group. Zimelidine shows additive analgesic effects when administered with morphine.

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Animal/Disease Models: SD (SD (Sprague-Dawley)) rats (150 to 250 g, 10 rats) [2]
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection one time/day for 14 days
Experimental Results: No changes in CA3 hippocampal pyramidal Neuronal responsiveness to microiontophoresis with 5-HT.

Absorption, Distribution and Excretion
This study investigated the pharmacokinetics of Zimeldine (a 5-HT reuptake inhibitor with antidepressant effects) after single and multiple oral doses in 19 male patients with alcohol dependence (10 with chronic liver injury and 9 without). The mean plasma concentration of Zimeldine in patients with chronic liver injury was significantly higher than that in patients without chronic liver injury, as assessed by AUC (area under the plasma concentration-time curve). The plasma half-life of Zimeldine was also significantly prolonged in patients with chronic liver injury. There were no differences in pharmacokinetic parameters between patients without chronic liver injury and healthy controls. The pharmacokinetics of the active metabolite norZimeldine (the N-demethylated product of Zimeldine) were also not different between the two groups of alcohol-dependent patients and healthy controls. IgA values were significantly correlated with both the AUC and plasma half-life of Zimeldine. No other correlations were found between clinicochemical parameters and the pharmacokinetic parameters of Zimeldine and norZimeldine. A crossover design was used, with five healthy adults receiving either oral (150 mg) or intravenous (20 mg) Zimeldine. Blood and urine samples were collected within 28 hours of administration to determine the concentrations of Zimeldine and norZimeldine. There was no significant difference in the terminal half-life of Zimeldine between oral (4.7 h ± 1.3 SD) and intravenous (5.1 h ± 0.7 SD) administration. An average of 50% of the oral dose entered systemic circulation. The average amount of unchanged Zimeldine excreted in urine was 1.26% of the intravenously administered dose. Zimeldine appears to be completely absorbed from the gastrointestinal tract, but its bioavailability is reduced to 50% by first-pass metabolism in the liver. The mean plasma half-life of norZimeldine was 22.8 hours. The area under the plasma concentration-time curve after oral administration of norZimeldine was 92% of that after intravenous administration. Plasma concentrations of Zimeldine and norZimeldine are expected to reach steady state within 3–5 days. This study determined the pharmacokinetics of a single oral dose of 200 mg Zimeldine (Z) and its demethylated metabolite norZimeldine (NZ) in six healthy volunteers (Group I). Simultaneously, studies were also conducted in patients with mild renal failure (Group II) and severe renal failure (Group III). Plasma and urine concentrations of Z and NZ were serially determined by high-performance liquid chromatography (HPLC) over 6 days post-dose. In Group I, Z was rapidly absorbed and metabolized to NZ, followed by a decrease in plasma concentration; the apparent elimination half-lives of Z and NZ were 8.4 hours and 24.9 hours, respectively. Renal clearance of both compounds was low, at 15.7 mL/min for Z and 33.0 mL/min for NZ. The plasma concentrations of Z did not differ significantly between groups I and III, but the area under the curve (AUC) in group III was significantly higher than that in group I (AUC 0-144 ≈ 17.3 μmol·L·h and 6.8 μmol·L·h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ, but significantly prolonged the time to peak concentration, apparent elimination half-life, and AUC. Renal clearance of NZ was significantly negatively correlated with plasma creatinine. Since NZ and Z have comparable pharmacological activities, these results suggest that the dose of Z should be reduced in patients with severe renal impairment. Metabolites/Metabolites: Twelve patients with depression were given the novel drug Zimeldine (50-300 mg/day). After approximately 3 weeks, the plasma concentrations of the demethylated metabolite, norZimeldine, were almost three times that of the parent drug. …
Several metabolites of (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine (Zimeldine) were isolated from urine in rats and dogs after administration of the 14C-labeled drug. The major metabolic pathways found in these species included oxidation of aliphatic and aromatic nitrogen, N-demethylation, and deamination of aliphatic nitrogen. The major excretion products in rat and dog urine were N-oxides of Zimeldine, the deamination product 3-(4-bromophenyl)-3-(3-pyridyl)acrylic acid, and its N-oxide. Clearly, there are only minor differences in the metabolism of Zimeldine between rats and dogs. N-oxides and acrylic acid derivatives of Zimeldine were also detected in human urine samples. Zimeldine is labeled with 14C at the allyl site. Most metabolites were synthesized as pure diastereomers, and their configurations were determined by UV spectroscopy and 1H NMR spectroscopy. The biological half-life of the parent compound was 8.4 ± 2.0 hours, and that of norZimeldine was 19.4 ± 3.6 hours. This study investigated the pharmacokinetics of Zimeldine (a 5-HT reuptake inhibitor with antidepressant effects) in 19 alcoholic men (10 with chronic liver injury and 9 without). …The plasma half-life of Zimeldine was also significantly prolonged in patients with chronic liver injury. A crossover design was used, with 5 healthy adults receiving oral (150 mg) and intravenous (20 mg) Zimeldine, respectively. Blood and urine samples were collected within 28 hours after administration, and the concentrations of Zimeldine and norZimeldine were determined. There was no significant difference in the terminal half-life of Zimeldine after oral administration (4.7 hours ± 1.3 SD) or intravenous administration (5.1 hours ± 0.7 SD). ... The mean plasma half-life of norZimeldine was 22.8 hours.

Interactions
This study investigated the acute interactions of Zimeldine (Z) and ethanol (E) in six healthy men aged 20 to 37 years. Participants were randomized to receive four different treatments, each one week apart: 200 mg Z orally followed by ethanol 1 hour before Z administration, and then ethanol dissolved in fruit juice 7 hours later, maintaining blood alcohol concentrations between 800 and 1000 mg/L; placebo Z and ethanol; Z and fruit juice; and placebo Z and fruit juice. Ethanol reduced the bioconversion of Z to norZimeldine (NZ) by 46%, but did not alter the area under the curve (AUC) of Z, NZ, or their total concentrations over 8 hours. Acetaldehyde concentrations remained unchanged, and no unpleasant alcohol sensitization was detected. The impairments in memory, body swaying, and manual tracking tasks, as well as the decrease in friendliness induced by ethanol, were further amplified by Z. Data indicate that Z and E interact kinetically and dynamically, suggesting a mechanism by which Z may reduce human E intake.

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Non-human toxicity values
Mouse intravenous LD50 60 mg/kg / From table/
Mouse oral LD50 800 mg/kg / From table/
Rat intravenous LD50 50 mg/kg / From table/
Rat oral LD50 900 mg/kg / From table/

[1]. Heel RC, et al. Zimelidine: a review of its pharmacological properties and therapeutic efficacy in depressive illness. Drugs. 1982 Sep;24(3):169-206.
[2]. Blier P, et al. Electrophysiological investigations on the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat. J Neurosci. 1983 Jun;3(6):1270-8.
[3]. Ozdemir E, et al. Zimelidine attenuates the development of tolerance to morphine-induced antinociception. Indian J Pharmacol. 2012 Mar;44(2):215-8.
[4]. Scopinho AA, et al. Medial amygdaloid nucleus 5-HT₂c receptors are involved in the hypophagic effect caused by zimelidine in rats. Neuropharmacology. 2012 Aug;63(2):301-9.

Zimeldine belongs to the styrene class of compounds. Zimeldine has been banned globally because it can cause severe, sometimes fatal, central and/or peripheral neuropathy, known as Guillain-Barré syndrome, and a specific hypersensitivity reaction affecting multiple organs, including rash, flu-like symptoms, arthralgia, and sometimes eosinophilia. Furthermore, Zimeldine has been accused of increasing suicidal ideation and/or suicidal behavior in patients with depression. Zimeldine is a selective serotonin reuptake inhibitor that was once used to treat depression, but was withdrawn from the market globally in September 1983 due to the risk of Guillain-Barré syndrome. (Excerpt from Martindale Pharmacopeia, 29th edition, p. 385) Drug Indications For the treatment of depression. Mechanism of Action The antidepressant effect of Zimeldine is believed to be related to its inhibition of serotonin uptake by neurons in the central nervous system. Zimeldine blocks the reuptake of serotonin by the serotonin reuptake pump on the neuronal membrane, thereby enhancing the effect of serotonin on its own receptors, 5-HT1A. Compared to tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) have significantly reduced affinity for histamine, acetylcholine, and norepinephrine receptors.

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Therapeutic Use
In a 4-week, double-blind study, researchers compared the efficacy of Zimeldine 200 mg and amitriptyline 150 mg in 32 outpatients with major depressive disorder. Assessment tools included the Hamilton Depression Rating Scale, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, and the Wakefield Self-Rating Depression Scale. Both drugs were effective for depression; however, Zimeldine appeared to have a slower onset of action for depressive and anxiety symptoms than amitriptyline. Although both drugs significantly improved insomnia symptoms during the study, amitriptyline appeared to be superior to Zimeldine and more effective in inducing sleep. Amitriptyline causes more autonomic and cardiovascular side effects, including tremors, drowsiness, and diarrhea; while Zimeldine causes tension, headache, nausea, joint pain, and decreased appetite, and appears to have an adverse effect on sleep. Four cases of hypersensitivity reactions were reported with Zimeldine. The conclusion is that the main difference between Zimeldine and amitriptyline is the fewer side effects. Decreased appetite may be therapeutically significant, as weight gain is a major challenge for patients taking antidepressants long-term. Due to its association with Guillain-Barré syndrome, Zimeldine has been withdrawn from the market globally for further investigation. /Previous Uses/

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Drug Warnings
Because Zimeldine can cause serious, sometimes fatal, central and/or peripheral neuropathy (i.e., Guillain-Barré syndrome), and a specific hypersensitivity reaction involving multiple organs (including rash, flu-like symptoms, joint pain, and sometimes eosinophilia), it has been banned worldwide. Furthermore, Zimeldine has been accused of increasing suicidal ideation and/or suicidal behavior in patients with depression. After its discontinuation, fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) successively replaced it, and other selective serotonin reuptake inhibitors (SSRIs) were subsequently introduced. This article reviews 13 cases of Guillain-Barré syndrome, all of which had a similar association with recent initiation of treatment with the antidepressant zimeldine. Patients taking zimeldine had an approximately 25-fold increased risk of developing Guillain-Barré syndrome compared to the natural incidence rate. The described cases provide strong evidence that Guillain-Barré syndrome may be a specific complication of drug treatment, likely immune-mediated. A small group of patients who had successfully received lithium treatment for many years were treated with zimeldine to determine whether this antidepressant could replace lithium in the treatment of bipolar disorder. No patients reached the planned 6-month treatment period due to depression, hypomania, mania, or abnormal adverse reactions. The results of this preliminary study suggest that patients with bipolar disorder currently receiving lithium treatment should not use antidepressants, including potent and selective serotonin reuptake inhibitors.

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Pharmacodynamics
Zimeridin is the first marketed selective serotonin reuptake inhibitor (SSRI) antidepressant. It is a pyridylallylamine drug with a structure different from other antidepressants.

C16H17BRN2

317.23

316.057

56775-88-3

Zimelidine dihydrochloride;60525-15-7

5365247

Typically exists as solid at room temperature

1.3±0.1 g/cm3

412.8±45.0 °C at 760 mmHg

203.4±28.7 °C

0.0±1.0 mmHg at 25°C

1.597

4.63

0

2

4

19

293

0

CN(C)C/C=C(/c1ccc(cc1)Br)\c2cccnc2

OYPPVKRFBIWMSX-SXGWCWSVSA-N

InChI=1S/C16H17BrN2/c1-19(2)11-9-16(14-4-3-10-18-12-14)13-5-7-15(17)8-6-13/h3-10,12H,11H2,1-2H3/b16-9-

(Z)-3-(4-bromophenyl)-N,N-dimethyl-3-pyridin-3-ylprop-2-en-1-amine

A-23140; A 23140; Zimelidine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)