Citalopram

CELEXA · cipram · ZD-211 · LU-10-171 · Ciprarnil · NITALAPRAM · CITALOPRAM · Nitalapram HBr

Identifikatoren & physikalische Daten

CAS No.	59729-33-8
Summenformel	C20H21FN2O
Durchschnittliche Molmasse	324,4 g/mol
Monoisotopische Masse	324,16379146 g/mol
SMILES	CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
InChIKey	WSEQXVZVJXJVFP-UHFFFAOYSA-N
PubChem CID	2771
ChEMBL	CHEMBL1628605
ChEBI	CHEBI:77397
EC No.	261-891-1
DTXSID	DTXSID8022826
Lokaler Name	Citalopram

Chemische & physikalische Eigenschaften

XLogP	3,2
Polarare Oberfläche (TPSA)	36,3
H-Brücken-Donoren	0
H-Brücken-Akzeptoren	4
Frei drehbare Bindungen	5
Schwere Atome	24
Formalladung	0
Komplexität	466
LogP (Verteilungskoeffizient)	3.76
LogS	-4.7
Color/Form	Fine white to off-white powder
Löslichkeit	Sparingly solublelog Kow = 1.39 at 22 °C.Solubility in water = 15,460 mg/L at 22 °C /Citalopram hydrobromide/... Sparingly soluble in water and soluble in ethanol.Methanol (Slightly), Water (Slightly)
Siedepunkt	347-358BP: 175-181 °C at 0.03 mm Hg /Citalopram/bp0.03 175-181°
Decomposition	When heated to decomposition it emits very toxic fumes of /nitrogen oxides, hydrogen fluoride and hydrogen bromides/
Schmelzpunkt	182-188Crystals from isopropanol. MP: 182-183. Freely soluble in water, ethanol, chloroform /Citolapram hydrobromide/178 °C156-157 °C
Optical Rotation	Specific optical rotation: +12.33 at 25 °C/D (c = 1 in methanol) /Citolapram escitalopram/
Physical Description	Solid
Stability/Shelf Life	Stable under recommended storage conditions. /Citalopram hydrobromide/
Dissociation Constants	9.389.78
Kovats Retention Index	2393.42408.62406.52391.3
Dichte	1.18±0.1 g/cm3(Predicted)
Lagerbedingungen	Sealed in dry,2-8°C
pKa (Säurekonstante)	pKa 9.38(H2O) (Uncertain)
Aggregatzustand	Solid
Farbe	White to Off-White
CAS Datenbank	59729-33-8(CAS DataBase Reference)
NIST chemische Informationen	Citalopram(59729-33-8)

Sicherheit & Vorschriften

GHS-Einstufung	This chemical does not meet GHS hazard criteria for 20% (1 of 5) of reports.WarningH302 (60%): Harmful if swallowed [Warning Acute toxicity, oral]H312 (20%): Harmful in contact with skin [Warning Acute toxicity, dermal]H315 (20%): Causes skin irritation [Warning Skin corrosion/irritation]H317 (40%): May cause an allergic skin reaction [Warning Sensitization, Skin]H319 (40%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]H332 (20%): Harmful if inhaled [Warning Acute toxicity, inhalation]H335 (20%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposureRespiratory tract irritation]H361 (20%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]H410 (40%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]P203, P261, P264, P264+P265, P270, P271, P272, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P333+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 5 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Reported as not meeting GHS hazard criteria per 1 of 5 reports by companies.There are 3 notifications provided by 4 of 5 reports by companies with hazard statement code(s).Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.
Regulatorische Informationen	Status: Active Update: 24-07-2020 https://echa.europa.eu/registration-dossier/-/registered-dossier/22357Citalopram: Does not have an individual approval but may be used under an appropriate group standard
FDA-Anforderungen	The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including citalopram hydrobromide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Citalopram hydrobromide/
Toxic Combustion Products	Special hazards arising from the substance or mixture: Carbon oxides, nitrogen oxides (NOx), hydrogen bromide gas, hydrogen fluoride. /Citalopram hydrobromide/
Hazard Classes and Categories	Acute Tox. 4 (60%)Acute Tox. 4 (20%)Skin Irrit. 2 (20%)Skin Sens. 1 (40%)Eye Irrit. 2 (40%)STOT SE 3 (20%)Repr. 2 (20%)Aquatic Chronic 1 (40%)
Hazardous Reactivities and Incompatibilities	Incompatible materials: Strong oxidizing agents. /Citalopram hydrobromide/
Brandbekämpfungsverfahren	Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Citalopram hydrobromide/Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Citalopram hydrobromide/
Lagerbedingungen	Store at 20 °C to 25 °C (68 °F to 77 °F)excursions permitted from 15 °C to 30 °C (59 °F to 86 °F).Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2-8 °C. /Citalopram hydrobromide/
Reinigungsverfahren	ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Citalopram hydrobromide/
Entsorgungsverfahren	SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. /Citalopram hydrobromide/
Preventive Measures	ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust. Environmental precautions: Do not let product enter drains. /Citalopram hydrobromide/Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Citalopram hydrobromide/Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Citalopram hydrobromide/Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Citalopram hydrobromide/SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.
Personal Protective Equipment (PPE)	Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Citalopram hydrobromide/Skin protection: Handle with gloves. /Citalopram hydrobromide/Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Citalopram hydrobromide/Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Citalopram hydrobromide/
Körperbelastung	... In 22 /postmortem/ cases studied, heart blood citalopram conc ranged from 0.09 to 1.64 mg/L (n = 22, mean +/- SD = 0.51+/-0.43, median = 0.34)femoral blood conc ranged from 0.09 to 0.76 mg/L (n = 14, mean +/- SD = 0.34+/-0.23, median = 0.28)and urine conc ranged from 0.05 to 276.00 mg/L (n = 13). Liver was analyzed in three cases with citalopram concn ranging from 2.22 to 8.08 mg/kg. The average heart blood/femoral blood ratio was 1.26 (range 0.75 to 1.98, n = 14). In each case, the cause of death was not considered to be related to citalopram toxicity. ... /Salt not specified/
Treatment	Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of citalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Celexa. (L1712)
Wechselwirkungen	The aim of this study was to investigate the drug-drug interaction between carvedilol and citalopram based on carvedilol metabolism in vitro and his pharmacokinetics (PKs) in vivo after the oral administration of the single drug and both drugs, and reveal citalopram effects on the PKs of carvedilol. Each rat was cannulated on the femoral vein, prior to being connected to BASi Culex ABC. Carvedilol was orally administrated in rats (3.57 mg/kg body weight (bw)) in the absence of citalopram or after a pre-treatment with multiple oral doses of citalopram (1.42 mg/kg b.w.). Plasma concentrations of carvedilol were determined using high-performance liquid chromatography-MS at the designated time points after drug administration, and the main PK parameters were calculated by noncompartmental analysis. In addition, effects of citalopram on the metabolic rate of carvedilol were investigated using rat-pooled liver microsome incubation systems. During co-administration, significant increases of the area under the plasma concentration-time curve as well as of the peak plasma concentration were observed. The rat-pooled liver microsome incubation experiment indicated that citalopram could decrease the metabolic rate of carvedilol. Citalopram co-administration led to a significant alteration of carvedilol's PK profile in ratsit also demonstrated, in vitro, these effects could be explained by the existence of a drug-drug interaction mediated by CYP2D6 inhibition.... A case involving a fatality due to the combined ingestion of two different types of antidepressants /is presented/. A 41-year-old Caucasian male, with a history of depression and suicide attempts, was found deceased at home. Multiple containers of medication, /including/ citalopram (Cipramil) ... as well as a bottle of whiskey were present at the scene. The autopsy findings were unremarkable, but systematic toxicological analysis ... revealed citalopram (and metabolite) /among others/. ... A new liquid chromatographic separation /was developed/ ... and the results obtained for blood and urine, respectively, were /for/ desmethylcitalopram 0.42 ug/mL and 1.22 ug/mL& /for/ citalopram 4.47 ug/mL and 19.7 ug/mL /among others/. The cause of death was attributed to the synergistic toxicity of moclobemide and citalopram ... /which/ can produce a potentially lethal hyperserotoninergic state ...The purpose of this study was to evaluate the influence of tobacco smoke on the pharmacokinetics of citalopram (CIT) and desmethylcitalopram (DCIT) and its enantiomers on an animal model. High performance liquid chromatography (HPLC) with a diode array detector (DAD) was used for the identification and quantification of the studied compounds. The HPLC quantification of racemic mixtures of CIT was performed on a C18 column. The limits of detection (LOD) and quantification (LOQ) were: 7 and 10 ng/mL respectively. HPLC separation of citalopram enantiomers (S- and R-CIT) was performed on a Chirobiotic V column. The limits of detection (LOD) and quantification (LOQ) were: 6 and 15 ng/mL for R- and S-CIT respectively. The experiment was carried out on male Wistar rats. The rats were exposed to tobacco smoke for five days (6 hours per day). After the exposure, citalopram was administered in a dose of 10 mg/kg intragastrically. In the control group (non-exposed animals), citalopram was administered in the same way and at an equal dose. The blood of the animals was collected at nine time points. It was found that tobacco smoke exposure inhibits the biotransformation of citalopram. The half-life of the racemic mixture of citalopram after intragastric administration was increased by about 287%. Changes in the pharmacokinetic parameters of S-citalopram (active isomer) show a similar tendency to those of the racemic mixture. The pharmacokinetics of R-citalopram showed no statistically important differences after tobacco smoke exposure. Alterations in the pharmacological parameters of desmethylcitalopram presented an opposite trend to the parent drug. After exposure to tobacco smoke, the induction of metabolism of this compound was observed.Use of selective serotonin-reuptake inhibitors (SSRIs) such as citalopram concurrently or in close succession with other drugs that affect serotonergic neurotransmission may result in potentially life-threatening serotonin syndrome. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea). The precise mechanism of serotonin syndrome is not fully understoodhowever, it appears to result from excessive serotonergic activity in the CNS, probably mediated by activation of serotonin 5-HT1A receptors. The possible involvement of dopamine and 5-HT2 receptors also has been suggested, although their roles remain unclear.For more Interactions (Complete) data for Citalopram (34 total), please visit the HSDB record page.
Ökotoxizitätswerte	EC50Species: Pseudokirchneriella subcapitata (Green Algae) exponential growth phase, 10000 cells/mLConditions: freshwater, static, 18 °C, pH 8.1-8.5Concentration: 1600 ug/L for 48 hrEffect: decreased population growth rate /formulation/Species: Daphnia magna (Water Flea) age <24 hrConditions: freshwater, static, 18-22 °CConcentration: 20000 ug/L for 48 hrEffect: intoxication, immobilization /formulation/
Umweltverhalten	TERRESTRIAL FATE: Based on a classification scheme(1), log Koc values of 5.47 to 6.02(2) indicate that citalopram is expected to be immobile in soil(SRC). The pKa of citalopram is 9.78(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Citalopram is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Using an activated sludge inoculum, citalopram was not biodegraded in 28 days(6), indicating biodegradation is not an important environmental fate process in soil(SRC).AQUATIC FATE: Based on a classification scheme(1), log Koc values of 5.47 to 6.02(2) indicate that citalopram is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 9.78(3) indicates citalopram will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), BCF values of <7 to 41(5) suggest that bioconcentration in aquatic organisms is low(SRC). Using an activated sludge inoculum, citalopram was not biodegraded in 28 days(6), indicating biodegradation is not an important environmental fate process in water(SRC).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), citalopram, which has an estimated vapor pressure of 1.1X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase citalopram is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC)the half-life for this reaction in air is estimated to be 4 hrs(SRC), calculated from its rate constant of 9.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase citalopram may be removed from the air by wet and dry deposition(SRC). An aquatic photolysis half-life of 39 days was measured using citalopram hydrochloride in lake water under simulated sunlight conditions(3) suggesting that citalopram may be susceptible to direct photolysis by sunlight(SRC).
Unerwünschte Wirkungen	Reports suggest that adverse reactions occur in up to 10% of patients.Most Common Adverse Effects* CNS: Drowsiness, insomnia, dizziness, headache (dose-dependent)* Dermatologic: Diaphoresis* Gastrointestinal: Nausea, vomiting, xerostomia, constipation, diarrhea* Sexual: Ejaculation disorder (dose-dependent)Less Common Adverse Effects* Cardiovascular: Myocardial infarction, prolonged QT interval, Torsades de pointes* Hematologic: Hemorrhage, abnormal* Neurologic: Cerebrovascular accident* Psychiatric: Suicidal ideation, suicide, induction of mania* Other: Serotonin syndromeHyponatremia resulting from SIADH is a rare adverse effect. Citalopram has been shown to induce hyponatremia in case reports involving older patients. In addition to advanced age, other factors such as female gender, concurrent diuretic use, low body weight, and recent pneumonia may increase the likelihood of hyponatremia.Evidence indicates a direct correlation between the dosage and the severity of adverse effects such as impotence, fatigue, somnolence, insomnia, sweating, and yawning.Abrupt Discontinuation of AntidepressantAntidepressant discontinuation syndrome commonly results when patients suddenly stop antidepressant therapy. The most common discontinuation syndrome symptoms include nausea, vomiting, diarrhea, headaches, light-headedness, dizziness, diminished appetite, sweating, chills, tremors, fatigue, somnolence, and sleep disturbances. Less common symptoms include electric shock-like sensations, cardiac arrhythmias, myalgia, arthralgia, and balance difficulties. Due to these adverse effects, gradual tapering of the antidepressant therapy over several weeks to several months (based on the treatment duration) is strongly recommended. The half-life of drugs and duration of the therapy should factor in these decisions, as antidepressants with a shorter half-life may need to be tapered more conservatively.Citalopram hydrobromide is correlated with suicidality and worsening depression, especially in children, adolescents, and young adults (younger than 24). Antidepressants may elevate the risk of suicidal ideation in children, adolescents, and young adults when compared to placebo administration. The decision to use citalopram hydrobromide or any other antidepressant in children through young adults depends on the patient's specific condition and the clinician's judgment, weighing the potential benefits and risks on a case-by-case basis.Patients of any age who start antidepressant therapy should be monitored and observed closely for clinical deterioration, suicidality, or unusual behavior changes. Citalopram hydrobromide is not FDA-approved for use in pediatric patients.Increased risk of suicidal ideation and treatment-emergent suicidal ideation (TESI) are concerns in younger patients at the onset of therapy. However, an analysis of 17 controlled clinical trials comprising 5000 patients who were treated with citalopram, a tricyclic antidepressant, another SSRI, or a placebo revealed that the citalopram group had the lowest incidence of suicide. Furthermore, family and twin studies offer evidence of a genetic influence on suicidal behavior, leading to the hypothesis that genetic factors may also contribute to TESI.
Expositionspfade	Rapidly and well absorbed from the GI tract. Peak plasma concentrations occur within 4 hours of a single orally administered dose. Bioavailability is 80% following oral administration. Food does not affect absorption.
Toxizitätsübersicht	IDENTIFICATION AND USE: Citalopram is a solid. It is a serotonin uptake inhibitor, and second-generation antidepressive agent. Citalopram tablets are indicated for the treatment of depression. HUMAN STUDIES: Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Five male infants exposed to citalopram (30 mg/day), paroxetine (10-40 mg/day) or fluoxetine (20 mg/day) during gestation exhibited withdrawal symptoms at or within a few days of birth and lasting up to 1 month. Symptoms included irritability, constant crying, shivering, increased tonus, eating and sleeping problems, and convulsions. Late gestational exposure to citalopram, may be associated with a neonatal toxicity syndrome with immediate onset at birth or soon after birth and sometimes may be mistaken for neonatal withdrawal syndrome. A 3860 g infant was delivered at 40 weeks gestation. The mother had been taking citalopram 20 mg/day until the day of delivery. Citalopram was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes. ANIMAL STUDIES: Citalopram was administered in the diet to mice and rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day doses. The relevance of these findings to humans is unknown. Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with cStudies reveal that citalopram toxicity is not common, even at doses up to 100 mg. However, there is a chance of developing serotonin hyperactivity at therapeutic doses, primarily if using another serotonergic medication concomitantly.In the event of an intentional overdose, the ingestion of more than 600 mg of citalopram requires 8 hours of cardiac monitoring. At the end of the observation period, the patient can be discharged if the patient is asymptomatic and QTc is less than 450 milliseconds. However, continued inpatient cardiac monitoring is necessary for patients with QTc greater than 450 milliseconds at the end of the observation period. Case reports also describe recurrent seizures associated with massive citalopram overdose. Seizures should be treated with benzodiazepines.Management of serotonin syndrome requires withdrawal of the citalopram and aggressive supportive treatment for hyperthermia and autonomic dysfunction. Cyproheptadine, a serotonin antagonist (5HT2 receptors), can be administered.The antidepressant, antiobsessive-compulsive, and antibulimic actions of citalopram are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Citalopram blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT<sub>1A</sub> autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.
Ökotoxizitätsauszüge	/AQUATIC SPECIES/ Psychoactive drugs, such as selective serotonin reuptake inhibitors (SSRI) have been identified in high levels in effluents from Swedish sewage treatment plants (STP) at concentrations high enough to give pharmacological effects in fish. In humans SSRIs are used in the treatment of depression and they have anxiolytic effects. In the present study ...Endler guppy (Poecilia wingei) of both sexes /were exposed/ to citalopram that showed the highest concentrations of SSRIs in STP effluents and studied reproductive and non-reproductive behavior. Male courting behaviors were not affected compared to control fish after 14-28 days exposure to 1 ug/L. In two experiments exposing both sexes to 0.2, 2.3 or 15 ug/L for 21 days, fish exposed to the two highest doses showed anxiolytic effects when placed in a novel environment (novel tank diving test, NT). Males were only affected by exposure to 15 ug/L. They had significantly longer latency to explore the upper half of the aquarium, more visits and longer time spent in the upper half, and showed less bottom freezing behavior, all markers of anxiolytic behavior. In females exposure to 2.3 or 15 ug/L significantly increased freezing behavior, while no effects on other behavior variables were observed. No effects on shoaling behavior could be discerned. These results show that citalopram have anxiolytic effects on guppy fish and thus affect ecologically relevant behaviors of importance to survival of fish./AQUATIC SPECIES/ Citalopram is an antidepressant drug, which acts by inhibiting the re-uptake of serotonin from the synaptic cleft into the pre-synaptic nerve ending. It is one of the most common drugs used in treatment of depression, it is highly lipophilic and frequently found in sewage treatment plant effluents and surface waters around the world. Citalopram and other selective serotonin re-uptake inhibitors have, at concentrations that occur in nature, been shown to have behavioral as well as physiological effects on fish and other animals. This study is the result of several different experiments, intended to analyse different aspects of behavioral effects of chronic citalopram exposure in fish. ...The three-spine stickleback is common in the entire northern hemisphere and is considered to be a good environmental sentinel species. Female three-spine sticklebacks were exposed to 0, 1.5 and 15 ug/L nominal concentrations of citalopram for 21 days and subjected to the novel tank (NT) diving test. In the NT test, the fish exposed to 1.5 ug/L, but not the 15 ug/L fish made a significantly higher number of transitions to the upper half and stayed there for significantly longer time than the fish exposed to 0 ug/L. The 15 ug/L group, however, displayed a significantly lower number of freeze bouts and a shorter total freezing time. The test for locomotor activity included in the NT test showed that fish treated with 1.5 and 15 ug/L displayed a significantly higher swimming activity than control fish both 5-7 and 15-17min after the start of the experiment. In the next experiment ...fish exposed to 1.5 ug/L and 0.15 ug/L /were compared/ to pure water controls with regard to shoaling intensity and found no effect of treatment. In the final experiment the propensity of fish treated with 1.5 ug/L to approach an unknown object and aggressive behavior was investigated using the Novel Object test and a mirror test, respectively. The exposed fish ventured close to the unknown/AQUATIC SPECIES/ In the present study, ...the toxicities of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) /were tested/ as single substances and of citalopram, fluoxetine, and sertraline in binary mixtures in two standardized bioassays. Test organisms were the freshwater algae Pseudokirchneriella subcapitata and the freshwater crustacean Daphnia magna. In algae, test median effect concentrations (EC50s) ranged from 0.027 to 1.6 mg/L, and in daphnids, test EC50s ranged from 0.92 to 20 mg/L, with sertraline being one of the most toxic compounds. The test design and statistical analysis of results from mixture tests were based on isobole analysis. It was demonstrated that the mixture toxicity of the SSRIs in the two bioassays is predictable by the model of concentration addition. Therefore, in risk assessment based on chemical analysis of environmental samples, it is important to include the effect of all SSRIs that are present at low concentrations, and the model of concentration addition may be used to predict the combined effect of the mixture of SSRIs./AQUATIC SPECIES/ In this investigation, the 48-hr acute toxicity of mixtures (binary and quaternary) of four common SSRIs (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], and citalopram [Celexa]) were determined in the daphnid Ceriodaphnia dubia. Logistic regression was used to model mortality data and to investigate the applicability of concentration addition and independent action models to explain observed mortality. The concentrations estimated to induce 50% mortality in 48 hr for the individual SSRIs sertraline, fluoxetine, paroxetine, and citalopram were 0.48 to 0.66, 1.23 to 1.84, 2.23 to 3.57, and 10.47 to 14.53 uM, respectively. Concentration addition was a better predictor of mixture effects than independent action and suggested that the tested SSRIs have a similar mechanism of action. Results indicate that environmental hazard assessments should be conservative and consider that acutely toxic effects in aquatic organisms can be additive for each SSRI in a mixture./AQUATIC SPECIES/ In this investigation, the acute and chronic toxicity of five SSRIs (fluoxetine, Prozacfluvoxamine, Luvoxparoxetine, Paxilcitalopram, Celexaand sertraline, Zoloft) were evaluated in the daphnid Ceriodaphnia dubia. For each SSRI, the 48-hr median lethal concentration (LC50) was determined in three static tests with neonate C. dubia, and chronic (8-day) tests were conducted to determine no-observable-effect concentrations (NOEC) and lowest-observable-effect concentrations (LOEC) for reproduction endpoints. The 48-hr LC50 for the SSRIs ranged from 0.12 to 3.90 mg/L and the order of toxicity of the compounds was (lowest to highest): Citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline. Mortality data for the 8-day chronic tests were similar to the 48-hr acute data. The SSRIs negatively affected C. dubia reproduction by reducing the number of neonates per female, and for some SSRIs, by reducing the number of broods per female. For sertraline, the most toxic SSRI, the LOEC for the number of neonates per female was 0.045 mg/L and the NOEC was 0.009 mg/L. Results indicate that SSRIs can impact survival and reproduction of C. dubiahowever, only at concentrations that are considerably higher than those expected in the environment.
Signs and Symptoms	Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, and sinus tachycardia. In more rare cases, observed symptoms included amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Withdrawal symptoms include flu-like symptoms, insomnia, nausea, imbalance, sensory changes and hyperactivity.
Effluent Concentrations	Citalopram was detected at a concentration of 260 ng/L in treated effluent from a Swedish municipal sewage treatment works(1). The compound was detected at 430,000 ng/L in undiluted effluent from the Patancheru Enviro treatment plant near Hyderabad, India which received process water from 90 bulk pharmaceutical manufacturers(2). Citalopram exhibited an 83% frequency of detection following an analysis of 90 European wastewater treatment plant effluents sampled in 2010. The maximum concentration was 189 ng/Laverage 33.8 ng/Ldetection limit = 5 ng/L(3). Citalopram was measured in raw wastewater at two wastewater treatment plants in the Grand River watershed in southern Ontario, Canada at mean concentrations of 0.223 and 0.136 ug/L in samples collected on August 27, 2007 and Nov 6, 2007, respectively. The mean concentration in treated wastewater was approximately 0.25 ug/L(4).
Soil Adsorption/Mobility	Using 3 soils (loamy sand (6.25% clay, 7.50% silt, 86.25% sand, 1.01 organic matter, pH 5.0), sandy loam (7.50% clay, 1.75% silt, 75.75% sand, 1.77 organic matter, pH 7.8) and loamy sand (5.00% clay, 8.50% silt, 86.50% sand, 0.93 organi matter, pH 7.8)) soils, log Koc values of 6.02, 5.47 and 5.58, respectively, were measured(1). A mean log Koc value of 3.84 was measured in agricultural soil from Corrstown, Co. Dublin Irelanda mean log Koc 2.96 was measured in sludge from a major wastewater treatment plant in Dublin, Ireland(2). A log koc of 5.63 has also been reported(3). According to a classification scheme(4), these Koc values suggest that citalopram is expected to be immobile in soil. log Koc values in sediment were 5.88 and 5.32 for a silt (0.00% clay, 92.75% silt, 7.25% sand, 0.16 organic matter, pH 6.7) and silt loam (7.50% clay, 66.25% silt, 26.25% sand, 0.65 organic matter, pH 5,6) sediments, respectively(1). The estimated pKa of citalopram is 9.78(5), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(6).
UN-Transportnummer	3249
Gefahrenklasse	6.1(b)
Verpackungsgruppe	III
Gefahrstoffdaten	59729-33-8(Hazardous Substances Data)

Anwendungen & Verwendung

Beschreibung

Citalopram is a specific serotonin-uptake inhibitor useful in the treatment of depression. In endogenous depression citalopram was reported to be as effective as amitriptyline and mianserin, while being inferior to clomipramine in both endogenous and non-endogenous depression.

History

The invention of citalopram dates back to 1972, when Klaus Bøgesø, a chemist at H. Lundbeck A/S in Denmark, and his team, while searching for new antidepressants, rationally designed and synthesized a compound called 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxynitrile, based on their previous research on the norepinephrine reuptake inhibitor talopram. They quickly completed a patent application, marking the pharmacological starting point for citalopram as a selective serotonin reuptake inhibitor (SSRI). In the late 1970s, the compound entered a systematic preclinical research phase, and its unique highly selective inhibition of the serotonin transporter (SERT) was gradually confirmed, exhibiting good antidepressant activity in animal models. In the early 1980s, citalopram entered clinical trials. Multiple double-blind controlled studies confirmed its significant efficacy and good tolerability for major depressive disorder. It was finally launched in Denmark in 1989 under the brand name Cipramil®, becoming the first domestically developed SSRI antidepressant in the Nordic market. In the 1990s, H. Lundbeck entered into a collaboration agreement with Forest Laboratories in the United States to jointly advance the registration of citalopram in the US. After a series of clinical trials that met FDA requirements, the drug received FDA approval on July 17, 1998, and officially entered the US market in September of the same year under the brand name Celexa®, quickly becoming one of the fastest-growing antidepressants in terms of prescription volume at the time. With the expiration of the citalopram patent in 2003, several generic drugs were launched, further expanding its global usage. This also spurred the development of its S-enantiomer, escitalopram, which was initiated in 1997 and approved in 2002, becoming Lundbeck's next-generation core antidepressant product.

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