Zimelidine

390.14500

317.22

DTXSID6048462

16.13000

5.44140

1.286g/cm3

196-199 °C

412.8ºC

203.4ºC

In water, 190 mg/L at 25 °C (est)

Desiccate at RT

2.6X10-6 mm Hg at 25 °C (est)

Henry's Law constant = 5.0X10-11 atm cu m/mole at 25 °C (est)

pKa1 = 4.41(puridine); pKa2 = 8.33 (amine) (est)

Hydroxyl radical reaction rate constant = 1.7X10-10 cu cm/molecule-sec at 25 °C (est)

R22

Xn

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The acute interaction of zimelidine (Z) with ethanol (E) was examined in six healthy men aged 20 to 37 yr who randomly received each of four treatments 1 wk apart: Z, 200 mg by mouth, preceded by 1 hr and followed for 7 hr of oral E in juice dosed to maintain blood alcohol concentrations between 800 and 1000 mg/L; placebo Z and E; Z and juice; and placebo Z and juice. E decreased the rate of biotransformation of Z to norzimelidine (NZ) by 46%, but the AUCs of Z, NZ, and their total concentration over 8 hr were not altered by E. Acetaldehyde concentrations did not change and no aversive alcohol-sensitizing reaction was detected. E-induced impairments in memory, body sway, and a manual tracking task were further enhanced by Z, as was the E-induced decrease in friendliness. Data suggest Z and E interact kinetically and dynamically and suggest a mechanism whereby Z may decrease E intake in man.

LD50 Mouse iv 60 mg/kg /from table/|LD50 Mouse oral 800 mg/kg /from table/|LD50 Rat iv 50 mg/kg /from table/|LD50 Rat oral 900 mg/kg /from table/

In a 4 wk double-blind study, zimeldine 200 mg was compared with amitriptyline 150 mg in 32 psychiatric outpatients with major depressive disorder. Assessment instruments included the Hamilton Depression scale, the Clinical Global Impression scale, the Hamilton Anxiety scale and Wakefield Self-Assessment Depression Inventory. Both drugs were efficacious in depression; however, zimeldine appeared to have a slower onset of action on the symptoms of depression and anxiety than amitriptyline. Although both drugs produced a significant improvement in insomnia over the course of the study, amitriptyline appeared to have a better effect than zimeldine and was more effective in sleep induction. Whereas amitriptyline produced more autonomic, cardiovascular side effects, tremor, drowsiness and diarrhea, zimeldine produced inner tension, headaches, nausea, arthralgia, and decreased appetite and appeared to adversely affect sleep. There were 4 episodes of hypersensitivity reaction with zimeldine. It was concluded that the major difference between zimeldine and amitriptyline relates to the decrease in side effects noted with zimeldine. The decrease in appetite may be therapeutically useful as weight gain is a major difficulty encountered in patients with long-term antidepressant therapy. Because of the association of Guillain-Barre syndrome with the zimeldine hypersensitivity reaction, the drug was withdrawn worldwide for further study. /Former use/

Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barre syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients. After its ban, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs.|Thirteen cases of the Guillain-Barre syndrome are reviewed, all occurring with a similar relationship to recent commencement of treatment with the antidepressive drug zimeldine. The risk of developing Guillain-Barre syndrome was increased about 25-fold among patients receiving zimeldine, as compared with the natural incidence of the disorder. The cases described provide strong evidence that Guillain-Barre syndrome may occur as a specific, probably immunologically mediated, complication of drug therapy.|A small group of patients who had been successfully treated with lithium for a number of years were treated with zimeldine in order to determine whether this antidepressant could be substituted for lithium in patients with a bipolar affective illness. The proposed treatment period of 6 months was not reached by any patient due to depression, hypomania, mania or unusual adverse symptoms. The results of this pilot study suggest that bipolar patients being treated with lithium should not then be treated by antidepressants including those which are potent and selective inhibitors of 5-HT uptake.

The occurrence of zimelidine, a new experimental antidepressant, in a sudden death is presented. Tissues were extracted with n-butyl chloride. Quantitation was done by capillary gas chromatography with a nitrogen/phosphorus detector. Drug confirmation was obtained by gas chromatography and mass spectrometry. Blood concentrations of zimelidine and its metabolite norzimelidine were 0.71 and 2.2 mg/L respectively. Concentrations of the drug and metabolite are also given for the urine, liver, bile, and brain.

The pharmacokinetics of zimeldine, a 5-HT reuptake blocker with antidepressive effects, was studied after a single oral dose and after multiple oral administration in 19 alcoholic males, 10 with and 9 without chronic liver damage. The average plasma concentration of zimeldine as assessed by the AUC values (area under the plasma concentration-time curve) was significantly higher in the chronically liver damaged patients than in the patients without chronic liver damage. The plasma half-life of zimeldine was also significantly longer in the chronically liver damaged patients. There were no differences in the obtained pharmacokinetic parameters between the patients having nonchronic liver damage and healthy control subjects. The pharmacokinetics of the active metabolite norzimeldine (resulting from N-demethylation of zimeldine) showed no differences between the two groups of alcoholics and the healthy controls. The IgA values were significantly correlated to both the AUC and plasma half-life of zimeldine. No other correlation between clinical chemistry parameters and pharmacokinetic parameters of zimeldine and norzimeldine were found.|Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 hr +/- 1.3 SD) or intravenous dosing (5.1 hr +/- 0.7 SD). An average of 50% of the ingested oral dose reached the systemic circulation. Excretion of unchanged zimelidine in urine was on average 1.26% of the intravenous dose. It appears that zimelidine is completely absorbed from the gastrointestinal tract and "first-pass metabolism" in the liver reduces the bioavailability to 50%. The mean plasma half-life for norzimelidine was 22.8 hr. The area under the plasma concentration time curve for norzimelidine after oral administration was 92% of that after intravenous administration. The plasma concentration of both zimelidine and norzimelidine are predicted to approach steady-state within 3-5 days.|The kinetics of zimeldine (Z) and its demethylated metabolite, norzimelidine (NZ), were determined after administration of a single 200 mg oral dose of Z to 6 healthy volunteers (Group I), and to patients with mild (Group II) and severe renal failure (Group III). Z and NZ concentrations were assayed by HPLC in serial plasma and urine samples over 6 days following the dose. In Group I Z was rapidly absorbed and metabolized into NZ, and then the plasma concentrations declined with apparent elimination half-lives of 8.4 h and 24.9 h for Z and NZ respectively, whilst the renal clearance of both compounds was low, Z 15.7 ml/min and NZ 33.0 ml/min. The plasma level of Z differed little between Groups I and III, but the area under the curve was significantly higher in Group III than in Group I subjects (AUC0-144 = 17.3 and 6.8 mumol X l-1 X h, respectively). Severe renal failure did not affect the peak plasma concentration of NZ but it did significantly increase peak time, apparent elimination half-life, and the area under the plasma concentration curve. A significant inverse relationship was found between renal clearance of NZ and plasma creatinine. Since NZ is as pharmacologically potent as Z, the results suggest that the dose of Z should be reduced in patients with severe renal insufficiency.

The novel drug zimelidine 50-300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. ...|Several metabolites of (Z)-3-(4-bromophenyl)-N,N-dimethyl-3-(3-pyridyl)allylamine (zimelidine) were isolated from urine of rat and dog after administration of the 14C-labelled drug. The major metabolic routes found in these species involve oxidations at both the aliphatic and aromatic nitrogen, N-demethylations and deamination of the aliphatic nitrogen. The major excretion products in urine from both rat and dog were the N-oxide of zimelidine, the deamination product 3-(4-bromophenyl)-3-(3-pyridyl)-acrylic acid and its N-oxide. Apparently, there are only minor differences between rat and dog in the metabolism of zimelidine. The N-oxide of zimelidine and the acrylic acid derivative were also identified in a human urine sample. Zimelidine was labelled with 14C in the allylic position. Most of the metabolites were synthesized in pure diastereomeric form and their configuration were shown by UV and 1H-NMR.

The pharmacokinetics of zimeldine, a 5-HT reuptake blocker with antidepressive effects, was studied after a single oral dose and after multiple oral administration in 19 alcoholic males, 10 with and 9 without chronic liver damage. ... The plasma half-life of zimeldine was also significantly longer in the chronically liver damaged patients.|Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 hr +/- 1.3 SD) or intravenous dosing (5.1 hr +/- 0.7 SD). ... The mean plasma half-life for norzimelidine was 22.8 hr.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ The side effects of an overdose in a 29-yr-old patient who had taken zimeldine, 5.2 g, were reported. The plasma concentration of zimeldine at 8 hr after admission was 11544 nmol/L, and that of nomelidine was 4233 nmol/L. After 6 days, the blood level of zimeldine was 0, and that of nomelidine was 675 nmol/L. Cardiovascular changes consisted only of tachycardia and prolongation of the PR interval, which resolved within 8 hr. Abdominal symptoms consisted of nausea and tenderness which persisted for 3 days. Effects on the nervous system included pupillary dilation, horizontal nystagmus, tremor, hypertonia and hyperreflexia, all of which resolved with 24 hr.|/CASE REPORTS/ Torsade de pointes tachycardias may occur in connection with overdoses, and more rarely with therapeutic doses, of tricyclic antidepressant agents and antiarrhythmic drugs, especially in the presence of hypokalemia. Zimeldine is a selective serotonin reuptake blocker, which according to studies in humans and animals, has no serious cardiovascular side effects in therapeutic doses. We report a patient who was admitted with repeated syncopal attacks resulting from prolonged QT intervals and torsade de pointes tachycardias. She also had hypokalemia, although she had had no treatment known to affect the potassium level. Correction of the potassium level rapidly prevented further tachycardias and led to normalization of the QT interval. Repeated blood samples verified high levels of zimeldine and its metabolites. We conclude that whenever torsade de pointes tachycardias occur, treatment with antidepressant or antiarrhythmic agents should be immediately suspected and verified. In addition, prompt initiation of potassium infusion may dramatically resolve the arrhythmias, even if the serum potassium level is within the lower normal range, and may also potentiate the effect of class I antiarrhythmic drugs such as lidocaine.|/CASE REPORTS/ Single episodes of grand mal convulsions occurring 4.5 to 5 hr after self-poisoning in 2 patients, aged 32 and 37 yr, who had taken zimelidine, 2 and 2.5 g, were reported. One patient had also taken 6 pints of beer (ethyl alcohol). Blood levels of zimelidine peaked at 4.8 and 4.7 mg/l and declined thereafter with half-lives of 3.6 and 4.9 hr, respectively. Blood levels of norzimeldine (nomelidine) declined more slowly. One patient was treated with diazepam, 5 mg IV, and both made an uneventful recovery.|/CASE REPORTS/ Adverse experiences during licensed treatment with the antidepressant serotonin (5-HT) reuptake inhibitor zimeldine in Sweden are presented. Data were obtained from a written inquiry of 694 patients and 67 reports to the Medical Products Agency. The spectrum of adverse symptoms was in agreement with those reported in previous studies on zimeldine. The most frequent adverse experiences were headache, nausea, myalgia, signs of liver function disturbance, arthralgia, neurological symptoms, fever and insomnia. No new case of the Guillain-Barre syndrome was found. The estimated frequency of the zimeldine-induced hypersensitivity syndrome (HSS), comprising fever, myalgia and/or arthralgia and signs of liver function disturbance, ranged from 1.4% to 13% in the inquiry and from 0.63% to 3.4% in the report part of the study. Adverse experiences usually had a considerably higher incidence during the first 6 weeks of zimeldine treatment than thereafter. This is in agreement with the clinical experience that most of the adverse reactions occur early during zimeldine treatment. However, a number of adverse experiences did occur with a later onset. This may justify a prolongation of the compulsory 4 weeks' testing of liver function that is required during licensed treatment. There were significantly fewer patients who developed fever among the patients who had experienced previous zimeldine treatment than among those who had not. Otherwise there was no statistically significant difference in frequency of adverse symptoms between these two groups. Consequently zimeldine treatment per se does not seem to predispose to development of an HSS or other types of adverse reactions during subsequent therapy.|For more Human Toxicity Excerpts (Complete) data for ZIMELDINE (10 total), please visit the HSDB record page.

Zimelidine has been banned worldwide due to serious, sometimes fatal, cases of central and/or peripheral neuropathy known as Guillain-Barre syndrome and due to a peculiar hypersensitivity reaction involving many organs including skin exanthema, flu-like symptoms, arthralgias, and sometimes eosinophilia. Additionally, zimelidine was charged to cause an increase in suicidal ideation and/or attempts among depressive patients. After its ban, it was succeeded by fluvoxamine and fluoxetine (derived from the antihistamine diphenhydramine) in that order, and the other SSRIs (Selective Serotonin Reuptake Inhibitors).