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At least 19 recordsLinked to original sources
PubMed1976

Measurement of clomipramine, N-desmethyl-clomipramine, imipramine, and dehydroimipramine in biological fluids by selective ion monitoring, and pharmacokinetics of clomipramine.

To quantitatively determine tricyclic antidepressant agents, we used a combined gas chromatograph/mass spectrometer system, and deuterium-labeled internal standards. Recovery exceeds 95% and the coefficient of variation is less than 4% for human whole-blood samples supplemented with 5 to 15 ng of clomipramine hydrochloride or 20 to 60 ng of dehydroimipramine hydrogen fumarate per milliliter. For both amines, the detection limit is 0.3 mug/liter; Six healthy volunteers who received a single oral dose of 50 mg of clomipramine hydrochloride showed peak drug concentrations in the blood 3 to 5 h after administration, ranging between 14.4 and 30.1 mug/liter. Plasma/whole blood concentration ratios varied from 0.70 to 1.20, and the cumulative renal elimination from 0 to 72 h is less than 0.2% of the dose. This method is suitable for in vivo bioavailability studies of unchanged clomipramine, dehydroimipramine, and imipramine after a single oral dose of as little as 25 mg.

Antidepressive Agents↗
PubMed1998

Intravenous clomipramine for obsessive-compulsive disorder refractory to oral clomipramine: a placebo-controlled study.

BACKGROUND: Uncontrolled reports suggest that intravenous clomipramine hydrochloride may be effective for patients with obsessive-compulsive disorder (OCD) who are nonresponsive to oral clomipramine. METHODS: Fifty-four patients with oral clomipramine-refractory OCD were randomized to receive 14 infusions of either placebo or clomipramine hydrochloride, starting at 25 mg/d and increasing to 250 mg/d. Ratings were conducted double-blind after infusion 14 among 54 patients, single-blind 1 week later among 39 patients, and nonblind 1 month later among 31 patients. Response was based on a Clinical Global Impressions rating of at least "much improved." RESULTS: Six (21%) of 29 patients randomized to receive intravenous (i.v.) clomipramine vs 0 of 25 patients given i.v. placebo were responders after 14 infusions (df = 1, P<.02). Dimensional ratings after infusion 14 revealed significant (P = .007) improvement on the National Institute of Mental Health-Obsessive-Compulsive Scale and the Clinical Global Impressions Scale (P = .03), but not the Yale-Brown Obsessive Compulsive Scale. One week later, all dimensional measures of OCD showed significant improvement. At 1 week post-i.v., 9 (43%) of 21 patients initially randomized to i.v. clomipramine and treated subsequently with oral clomipramine were responders, whereas 0 of 18 patients initially randomized to receive i.v. placebo and treated subsequently with several days of open-label i.v. clomipramine responded (df = 1, P<.002). Of the 31 patients assessed 1 month after i.v. infusion (treatment not controlled), 18 (58.1%) were responders. Intravenous clomipramine treatment was safe with no serious adverse consequences. CONCLUSIONS: Intravenous clomipramine is more effective than i.v. placebo for patients with OCD with a history of inadequate response or intolerance to oral clomipramine. Further study of this promising treatment for refractory OCD is needed.

Administration, Oral↗
PubMed1976

Determination of clomipramine and desmethyl-clomipramine in plasma or urine by the double-radioisotope derivative technique.

A double radioisotope derivative method was developed for the determination of clomipramine and desmethyl-clomipramine in plasma or urine. After addition of 14C-labeled clomipramine and desmethyl-clomipramine as internal standards and extractive isolation of both compounds, desmethyl-clomipramine is acetylated with [3H]acetic anhydride. The [3H]acetamide is separated from clomipramine by thin-layer chromatography and its radioactivity is measured. Clomipramine, extracted from the cilica gel, is reacted with trichloroethyl chloroformate. The urethane is saponified and decarboxylated. The resulting desmethyl-clomipramine is acetylated with [3H]acetic anhydride. The [3H]acetamide is purified by thin-layer chromatography and its radioactivity is measured. The sensitivity of the method is 15 mug/liter for clomipramine and 2 mug/liter for desmethyl-clomipramine. Its specificity was made sure by a cross-check with a gas chromatography-mass spectrometry technique.

Carbon Radioisotopes↗
PubMed1998

The pharmacokinetics of clomipramine and desmethylclomipramine in dogs: parameter estimates following a single oral dose and 28 consecutive daily oral doses of clomipramine.

Clomipramine is a tricyclic antidepressant that has been recommended for the treatment of canine compulsive disorder. The pharmacokinetics of clomipramine in dogs have not been reported. This study describes the pharmacokinetics of clomipramine and its active metabolite, desmethylclomipramine, in six male dogs. Serial blood samples were collected following both a single oral dose of clomipramine (3 mg/kg) and 28 consecutive daily oral doses (3 mg/kg q 24 h). In addition, 'peak' and 'trough' samples were taken throughout the 28-day dosing period. Plasma was assayed for total (free and protein-bound) clomipramine and desmethylclomipramine, using gas-chromatography with mass spectrometric detection. Various pharmacokinetic parameters were then determined. Following a single dose of clomipramine, time of maximum plasma concentration (tmax) of clomipramine was 0.75-3.1 h, maximum plasma concentration (Cmax) was 16-310 ng/mL and elimination half-life (t1/2el) was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/ mL and t1/2el was 1.2-2.3 h. Following multiple dosing, there was a numeric increase in these parameters; tmax of clomipramine was 3-8 h, Cmax was 43-222 ng/mL and t1/2el was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/mL and t1/2el was 1.2-2.3 h. Clinically significant differences between dogs and humans in the pharmacokinetics of oral clomipramine are discussed.

Administration, Oral↗
PubMed2000

Steady state concentrations of clomipramine and its major metabolite desmethylclomipramine in rat brain and serum after oral administration of clomipramine.

Twenty male Sprague-Dawley rats received five oral doses of clomipramine 20 mg/kg at 4-h intervals. The animals were decapitated 1, 2, 3, 5 and 12 h after the last dose for determination of clomipramine and desmethylclomipramine in serum and frontal cerebral cortex. Time dependent concentrations of clomipramine and desmethylclomipramine paralleled in serum and brain. Half-lives were similar in serum and brain with 7.8 versus 6.2 h and 5.5 versus 5.0 h for clomipramine and desmethylclomipramine, respectively. Absolute concentrations, however, were markedly higher in brain than in serum - 12.5 fold for clomipramine and 7.4 fold for desmethylclomipramine. The data indicate that serum and brain concentrations of clomipramine and its demethylated metabolite are rapidly exchanged between blood and brain. Assuming that blood and brain kinetics in man and rat are comparable, it is concluded that monitoring blood concentrations of clomipramine and desmethylclomipramine is a useful way to evaluate brain concentrations.

Administration, Oral↗
PubMed1985

Efficacy and tolerability of sustained-release clomipramine (Anafranil SR) in the treatment of phobias: a comparison with the conventional formulation of clomipramine (Anafranil).

This multicentre double-blind trial in general practice compared the efficacy and tolerability of the sustained-release formulation of clomipramine (Anafranil SR) with its conventional formulation (Anafranil) in the treatment of phobias. Patients were allocated at random to receive clomipramine 75 mg once daily as either the sustained-release or conventional formulation for 11 weeks following a 1-week dosage build-up period. Analysis of results from forty-six patients showed that the sustained release formulation of clomipramine 75 mg was as effective as the conventional formulation of clomipramine 75 mg in improving symptoms of phobia as assessed by a phobia inventory and global evaluation. Unwanted effects attributable to therapy were similar in both treatment groups but there were fewer withdrawals due to unwanted effects of the sustained release formulation of clomipramine 75 mg. It was concluded that the sustained-release formulation of clomipramine does offer advantages for patients requiring 75 mg clomipramine daily.

Adolescent↗
PubMed1991

Clomipramine in the treatment of patients with obsessive-compulsive disorder. The Clomipramine Collaborative Study Group.

Two double-blind studies at 21 centers evaluated the therapeutic efficacy, safety, and tolerability of up to 300 mg/d of clomipramine hydrochloride or an equivalent number of placebo capsules in the treatment of 520 patients with obsessive-compulsive disorder, of whom 239 had had the disorder for at least 2 years (study 1) and 281 had been ill for at least 1 year (study 2). On the two principal measures of the severity of the disorder, ie, the Yale-Brown Obsessive Compulsive Scale and the National Institute of Mental Health Global Obsessive Compulsive Scale, clomipramine was significantly more effective than placebo in both studies. The mean reduction in the Yale-Brown Obsessive Compulsive Scale score at the end of 10 weeks of treatment was 38% and 44% in studies 1 and 2, respectively, for the clomipramine-treated patients and 3% and 5% for the placebo-treated patients. The drug was also found to be superior on the basis of the physicians' and patients' evaluations of global therapeutic change. The most frequently observed adverse effects during clomipramine therapy were those typically associated with tricyclic antidepressant drugs. Although uncommon, the occurrence of seizures and elevated aminotransferase values are potentially serious side effects of clomipramine. Clomipramine was generally well tolerated and was effective in reducing obsessive and compulsive symptoms.

Adult↗
PubMed2005

A fatal clomipramine intoxication case of a chronic alcoholic patient: application of postmortem hair analysis method of clomipramine and ethyl glucuronide using LC/APCI/MS.

Toxicological investigations of postmortem specimens of a 26-year-old man were performed with the use of LC/APCI/MS. They revealed in the blood of the deceased clomipramine (9.49 microg/g) and its main metabolite norclomipramine (1.10 microg/g) at concentrations explaining the fatal outcome. The presence of these xenobiotics in a 12-cm-long strand of hair (clomipramine, 7.60 ng/mg in I segment; 4.19 ng/mg in II segment; 1.86 ng/mg in III segment; norclomipramine, 5.71 ng/mg in I segment; 9.71 ng/mg in II segment; 4.13 ng/mg in III segment) confirmed the fact obtained from the medical history that the deceased had been receiving clomipramine as an antidepressant for 1 year prior to his death. The analysis demonstrated ethanol in autopsy blood (2.5mg/ml) and urine (3.2mg/ml); ethyl glucuronide as a marker of chronic alcohol abuse was detected in the deceased's hair (0.44 ng/mg in I segment; 0.07 ng/mg in II segment; n.d. in III segment). These findings may suggest the contribution of alcohol in the mechanism of drug-ethanol interaction, which in consequence might have affected the biotransformation of clomipramine in the final period of his life and evoked the ultimate toxic effect.

Adult↗
PubMed2003

Multicenter double-blind randomized parallel-group clinical trial of efficacy of the combination clomipramine (150 mg/day) plus lithium carbonate (750 mg/day) versus clomipramine (150 mg/day) plus placebo in the treatment of unipolar major depression.

BACKGROUND: The therapeutic efficacy of adding lithium to an ongoing antidepressant in resistant depression is well known. However there is less data concerning the efficacy of giving lithium and antidepressant concurrently from the start of treatment. METHODOLOGY: The primary objective of this study was to compare the efficacy of a combination of clomipramine+lithium (C+L) with that of clomipramine+placebo (C+P) in-patients with unipolar major depression, during the first 11 days of treatment. Secondary objectives were the assessment of effectiveness after 6 weeks and assessment of the safety of the combination clomipramine and lithium carbonate. C+L and C+P groups were compared for 6 weeks in a multicenter randomized trial of 141 patients hospitalized with a DSM-IV diagnosis of major depression. Efficacy was evaluated using the standard MADRS and CGI scales. RESULTS: Analysis of the 'as treatment ITT' population showed: the percentage reduction in MADRS scores between D0 and D11 in this population was better in the C+L group but not statistically significant (C+L: 32.1 vs. C+P: 27.4, P=0.07). Nevertheless, the comparison of mean MADRS scores showed a significant difference in the C+L group on days 4 (C+L: 25.1 vs. C+P: 27.8) and 7 (C+L: 18.6 vs. C+P: 21.5), P<0.05, and approaching significance on day 11 (C+L: 14.6 vs. C+P 17.2, P=0.054). On day 7, the number of patients in total remission was threefold higher in the C+L group than in the C+P group (15 vs. 4%, P<0.05) and twofold on day 11 (29 vs. 14%, P<0.05). CGI severity score showed C+L was superior to C+P on days 4, 7 and 11 and CGI improvement score was better in C+L group on day 11 (P<0.05). After 6 weeks of treatment no statistical difference was found between the two groups from the clinical point of view. Safety based upon clinical and laboratory parameters was satisfactory in both groups during the 6 weeks of the study. LIMITATIONS: Patients with bipolar disorder, previously treated with clomipramine or with any other mood stabilizers during the previous week; or with suicide attempt during the current episode with a score > or =3 for item 10 of the MADRS were excluded from the study. CONCLUSION: The results of this study suggests that lithium slightly to moderately potentiates antidepressant treatment in unipolar non-refractory patients with severe major depression in the first days of treatment but not as significantly as for the bipolar population.

Administration, Oral↗
PubMed1980

Variation in plasma concentrations of clomipramine and desmethylclomipramine during clomipramine therapy.

To determine steady-state plasma concentrations of clomipramine and desmethylclomipramine and their 24-hour variability, 17 depressed patients meeting certain defined criteria have been given clomipramine at stated dosages, and blood samples taken for measurement of these concentrations by gas-liquid chromatography. Response to treatment has been recorded by serial Hamilton-rating-scale and Beck-inventory scores. The complete results available for 13 patients indicate considerable variation both within and between individual patients. After three weeks' treatment plasma clomipramine concentrations ranged more widely than those of desmethylclomipramine, and some patients failed to reach steady state after five weeks' therapy. No correlation between concentration profiles and clinical response has yet emerged, but patients responding best had plasma clomipramine levels between 80 and 100 ng/ml.

Adolescent↗
PubMed2002

Interaction of lithium with 5-HT(1B) receptors in depressed unipolar patients treated with clomipramine and lithium versus clomipramine and placebo: preliminary results.

Lithium is commonly used in combination with antidepressant drugs as a treatment for refractory depression; less often, it is used in non-resistant depression. The aim of this study was to examine the interaction of lithium with 5-HT(1B) receptors in 10 non-resistant unipolar depressed patients treated with clomipramine+lithium (C+L) vs. clomipramine+placebo (C+P). A mediation of the serotonergic system has been proposed in the literature to explain the clinical effect of lithium. Indeed, in a previous study of healthy human blood platelets, we demonstrated the interaction of lithium with adenylate cyclase activity coupled to 5-HT(1B) receptors. The functional activity of these receptors was measured by studying the inhibitory effect of L694,247, a 5-HT(1B) receptor agonist, on the adenylate cyclase activity determined by the production of cAMP. Using the same technique in the present study, we found that lithium significantly reduced the inhibition of adenylate cyclase activity induced by 5-HT(1B) receptor activation. This result confirms the specific interaction of lithium with 5-HT(1B) receptors. Moreover, a correlation between the percentage of 5-HT(1B) receptor-dependent adenylate cyclase inhibition and the clinical benefit of lithium was established, suggesting 5-HT(1B) receptors may be a target for the therapeutic effect of lithium.

Adenylyl Cyclase Inhibitors↗
PubMed1983

[Plasma levels of desmethylclomipramine and clomipramine at steady-state in the morning. Correlative analysis and prediction of theoretical blood clomipramine].

Clomipramine (CMI) was administered to eight patients, either as an antidepressive drug or, in two patients, as an antalgic drug (average age: 54 y.; average body surface area: 1,71 m2). These patients were treated with 20 to 150 mg, every day, for various lengths of time: min.; one week: max.; 7 years, till the day before the determination of plasma levels. The samples were drawn on patients, fasting, in the morning. Plasma levels of CMI, Desmethylclomipramine (DCMI) and Cortisol were dosed by means of High Performance Liquid Chromatography with U. V. detection.

Adult↗
PubMed1991

Clinical pharmacokinetics of clomipramine.

Clomipramine is a tricyclic antidepressant medication widely used in Western Europe. Its pharmacokinetics have been studied essentially in healthy volunteers. By combining published information obtained during observational studies, it has been possible to derive a fairly precise picture of the behaviour of both parent compound and main metabolite (demethyl-clomipramine) in humans. Clomipramine can be compared with amitriptyline or imipramine so far as its physicochemical properties are concerned. As a consequence, its pharmacokinetic profile is also similar to that observed for these 2 drugs. Clomipramine is well absorbed from the gastrointestinal tract, but undergoes an important first-pass metabolism to demethyl-clomipramine which is pharmacologically active and participates in both therapeutic and unwanted effects. Protein binding is high, and the apparent volume of distribution is very large (i.e. greater than 1000L). After reaching the systemic circulation, clomipramine is further biotransformed into demethyl-clomipramine, and both active principles are hydroxylated to metabolites which are further conjugated before being excreted in urine. Hydroxylation of parent drug and metabolite is under polymorphic genetic control by the same cytochrome P450 as debrisoquine and sparteine. The apparent elimination half-life of clomipramine is about 24h and that of demethyl-clomipramine, 96h. Accordingly, the time to reach steady-state for both active moieties is in general around 3 weeks. Various pathological or environmental factors influence the behaviour of clomipramine and demethyl-clomipramine. Patients genetically deficient in hydroxylation accumulate demethyl-clomipramine at high concentrations that can produce serious side effects and/or nonresponse. The same is true for the coadministration of neuroleptics, in particular phenothiazines. Smoking induces demethylation, whereas long term alcohol intake appears to reduce this metabolic pathway. Finally, age usually diminishes both demethylation and hydroxylation, leading to a lower daily dose of clomipramine in most elderly patients. Studies relating blood concentrations of clomipramine and demethyl-clomipramine are conflicting. However, analysis of the available information indicates that blood concentrations lower than 150 micrograms/L are usually associated with nonresponse, whereas those above 450 micrograms/L seldom lead to an improvement in the efficacy of therapy. As a consequence clomipramine, like the other tricyclics, is an antidepressant with a fairly narrow therapeutic range. This property, combined with a high interindividual variability, makes this class of drugs ideal candidates for blood concentration monitoring.

Clomipramine↗