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Taken from http://prozactruth.com/clomipramine.htm Anafranil (Clomipramine) Anafranil. Anafranil side effects, warnings, precautions, adverse effects, overdose, withdrawal symptoms and Anafranil natural alternatives. Before you begin the spiral down with these drugs, try giving your body what it really wants. Pharmacology
Clomipramine is a tricyclic agent with both antidepressant and antiobsessional properties. Like other tricyclics, clomipramine inhibits norepinephrine and serotonin uptake into central nerve terminals, possibly by blocking the membrane-pump of neurons, thereby increasing the concentration of transmitter monoamines at receptor sites. Clomipramine is presumed to influence depression and obsessive and compulsive behaviour through its effects on serotonergic neurotransmission. The actual neurochemical mechanism is unknown, but clomipramine's capacity to inhibit serotonin reuptake is thought to be important. Clomipramine appears to have a mild sedative effect which may be helpful in alleviating the anxiety component often accompanying depression. As with other tricyclic compounds, clomipramine possesses anticholinergic properties which are responsible for some of its side effects. It also has weak antihistamine and antiserotonin properties, lowers the convulsive threshold, potentiates the effect of norepinephrine and other drugs acting on the CNS, has a quinidine-like effect on the heart and may impair cardiac conduction. The action of clomipramine on the human EEG is one of desynchronization. It causes a persistent increase in the frequency of shifts into stage I sleep and produces marked reduction or suppression of rapid eye movement sleep (REM or paradoxical sleep) with partial recovery within 3 to 4 weeks and a rebound after drug withdrawal which appears to last approximately the same time. In normal human volunteers tricyclic antidepressants tend to produce a sedative effect accompanied by atropine-like symptoms and may produce some difficulty in concentrating and thinking. Absorption is rapid and complete after oral administration in man. Plasma levels usually peak 2 hours after dosage but much individual variation occurs. The plasma half-life after a single oral dose is approximately 21 hours. After 28 days of oral administration to patients in a daily dosage of 75 mg, plasma concentrations of clomipramine ranged from 17 to 70 ng/mL (mean=35.7 ng/mL). The concentration of the active metabolite, desmethylclomipramine, was about twice as high. Binding to serum proteins at 96 to 97% is very high and is practically concentration-independent within the therapeutic range. Clomipramine has a volume of distribution of approximately 12 L/kg bodyweight. Clomipramine is extensively metabolized in the body with hydroxylation, demethylation and N-oxidation being the quantitatively more important routes of metabolism. Owing to the lower clearance of clomipramine in plasma, elderly patients require lower doses of clomipramine than patients in younger age groups. As expected, the metabolites of clomipramine are quite similar to those of imipramine, all retaining the benzazepine structure. Two-thirds of clomipramine is excreted in the form of water-soluble conjugates in the urine and approximately one-third in the feces. After a 25 mg Taken from http://prozactruth.com/clomipramine.htm radiolabelled dose of clomipramine in 2 subjects, the urinary recoveries of clomipramine and desmethylclomipramine were about 2% and 0.5% of the total radioactivity, respectively. Indications
For the treatment of depression. Clomipramine also appears to have a mild sedative effect which may be helpful in alleviating the anxiety component often accompanying depression. For the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD). The obsessions and compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning. The effectiveness of clomipramine for long-term use (i.e. for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials. The physician who elects to use clomipramine for extended periods should periodically re-evaluate the long term usefulness of the drug for the individual patient. Contraindications
Patients who have known hypersensitivity to the drug or have known hypersensitivity to tricyclic antidepressants belonging to the dibenzazepine group. Clomipramine should not be given in conjunction with or within 14 days of treatment with a MAO inhibitor. Hypertensive crises, hyperactivity, hyperpyrexia, spasticity, severe convulsions or coma, and death have been reported in patients receiving such combinations. It is contraindicated during the acute recovery phase following myocardial infarction and in the presence of acute congestive heart failure. Clomipramine is contraindicated in patients with existing liver or kidney damage and should not be administered to patients with a history of blood dyscrasias. Clomipramine is contraindicated in patients with glaucoma, as the condition may be aggravated due to the atropine-like effects of the drug. Warnings
Seizures: Tricyclic agents are known to lower the convulsive threshold and clomipramine should, therefore, be used with extreme caution in patients with a history of convulsive disorders and other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold. Total daily doses should not exceed the recommended total daily dose (see Dosage). Concurrent administration of ECT and clomipramine may be hazardous and such treatment should be limited to pati nts for whom it is essential. Physicians should discuss with patients the risk of taking clomipramine while engaging in activities in which a sudden loss of consciousness could result in serious injury to the patient or others e.g. the operation of complex machinery, driving, swimming, or climbing. Taken from http://prozactruth.com/clomipramine.htm Cardiovascular: Tricyclic antidepressants, particularly in high doses, have been reported to produce sinus tachycardia, changes in conduction time and arrhythmias. A few instances of unexpected death have been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also been reported with drugs of this class. Therefore, clomipramine should be administered with extreme caution to patients with a history of cardiovascular disease, especially those who have a history of conduction disorders, those with circulatory lability and elderly patients. It also has a hypotensive action which may be detrimental in these circumstances. In such cases, treatment should be initiated at low doses with progressive increases only if required and tolerated, and the patients should be under close surveillance at all dosage levels. Monitoring of cardiac function and the ECG is indicated in such patients. Use in Concomitant Illness: Caution should be observed in prescribing clomipramine in hyperthyroid patients or in patients receiving thyroid medication conjointly. Transient cardiac arrhythmias have occurred in rare instances in patients who have been receiving other tricyclic compounds concomitantly with thyroid medication. Because of its anticholinergic properties, clomipramine should be used with caution in patients with increased intraocular pressure or a history of urinary retention, particularly in the presence of prostatic hypertrophy. Particularly in the elderly and in hospitalized patients the tricyclic antidepressants may give rise to paralytic ileus and, therefore, appropriate measures should be taken if constipation occurs. Caution is called for when employing clomipramine in patients with tumours of the adrenal medulla (e.g. pheochromocytoma, neuroblastoma) in whom the drug may provoke hypertensive crisis. Clomipramine should be kept in a safe place, well out of the reach of children. Pregnancy: Safe use in pregnant women has not been established. Withdrawal symptoms including tremors, convulsions, and respiratory depression have been reported in neonates whose mothers received tricyclic antidepressants during the third trimester of pregnancy. Therefore, it should not be administered to women of childbearing potential, or during pregnancy, unless, in the opinion of the physician, the expected benefit to the patient outweighs the potential risk to the fetus. Lactation: Since clomipramine passes into breast milk, nursing mothers receiving it should not breast-feed their infants. Precautions
Suicide: The possibility of a suicide attempt is inherent in depression with or without obsessive-compulsive disorder. These patients should be carefully supervised during treatment with clomipramine, and hospitalization or concomitant electroconvulsive therapy may be required. To minimize the risk of an intentional overdose by a depressed patient, prescriptions for clomipramine should be written for the smallest possible quantity of the drug consistent with good patient management. Taken from http://prozactruth.com/clomipramine.htm Psychosis, Mania-Hypomania, and other Neuropsychiatric Phenomena: In patients treated with tricyclic antidepressants, activation of latent schizophrenia or aggravation of existing psychotic manifestations in schizophrenic patients may occur; patients with manic-depressive tendencies may experience hypomanic or manic shifts; and hyperactive or agitated patients may become over-stimulated. A reduction in dose or discontinuation of clomipramine should be considered under these circumstances. In predisposed and elderly patients, tricyclic antidepressants may, particularly at night, provoke pharmacogenic (delirious) psychoses which disappear without treatment within a few days of withdrawing the drug. Since clomipramine may produce sedation, particularly during the initial phase of therapy, patients should be cautioned about the danger of engaging in activities requiring mental alertness, judgement and physical coordination. Cardiovascular: Before initiating treatment, it is advisable to check the patient's blood pressure, because individuals with hypotension or a labile circulation may react to the drug with a fall in blood pressure. Regular measurements of blood pressure should be performed in susceptible patients. Postural hypotension may be controlled by reducing the dosage or administering circulatory stimulants. ECG abnormalities have been observed in patients treated with clomipramine. The most common ECG changes were premature ventricular contractions (PVCs), ST-T wave changes, and abnormalities in intraventricular conduction. These changes were rarely associated with significant clinical symptoms. Nevertheless, caution is necessary in treating patients with heart diseases, as well as elderly subjects. In these patients cardiac function should be monitored and ECG examinations performed during long-term therapy. Gradual dose titration is also recommended. Hepatic Changes: Clomipramine has occasionally been associated with elevations in AST (SGOT) and ALT (SGPT) of potential clinical significance (i.e. values greater than 3 times the upper limit of normal). In the majority of cases, these enzyme elevations were not associated with other clinical findings suggestive of hepatic injury. Isolated cases of obstructive jaundice have been reported. Caution is indicated in treating patients with known liver disease, and periodic monitoring of hepatic function is recommended in such patients. Hematologic Changes: Isolated cases of bone marrow depression with agranulocytosis have been reported. Leukocyte and differential blood cell counts are recommended in patients receiving treatment with clomipramine over prolonged periods, and should be performed for patients who develop fever, an influenzal infection, or sore throat. In the event of an allergic skin reaction, clomipramine should be withdrawn. CNS: More than 30 cases of hyperthermia have been recorded by nondomestic post-marketing surveillance systems. Most cases occurred when clomipramine was used in combination with other drugs. When clomipramine and a neuroleptic were used concomitantly, the cases were sometimes considered to be examples of a neuroleptic malignant syndrome. Withdrawal Symptoms: A variety of withdrawal symptoms have been reported in association with abrupt discontinuation of clomipramine, including dizziness, nausea, vomiting, headache, malaise, sleep disturbance, Taken from http://prozactruth.com/clomipramine.htm hyperthermia and irritability. In addition, such patients may experience a worsening of psychiatric status. While the withdrawal effects of clomipramine have not been systematically evaluated in controlled trials, they are well known with closely related tricyclic antidepressants, and it is recommended that the dosage be tapered gradually and the patient monitored carefully during discontinuation. Metabolic Effects: Tricyclic antidepressants have been associated with porphyrinogenicity in susceptible patients. Renal Function: It is also advisable to monitor renal function during long-term therapy with tricyclic antidepressants. Dental Effects: Lengthy treatment with tricyclic antidepressants can lead to an increased incidence of dental caries. Endocrine Effects: As with certain other psychotherapeutic drugs, clomipramine elevates prolactin levels. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of clomipramine is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of neuroleptic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis: The available evidence is considered too limited to be conclusive at this time. Children: As clomipramine has not been studied in patients under 10 years of age, specific recommendations for use in this age group cannot be provided. The long-term effects of clomipramine on childhood growth and development have not been determined. Drug Interactions: Patients should be warned that, while taking clomipramine, their responses to alcoholic beverages, other CNS depressants (e.g. barbiturates, benzodiazepines or general anesthetics) or anticholinergic agents (e.g. atropine, biperiden, levodopa) may be exaggerated. When tricyclic antidepressants are given in combinations with anticholinergics or neuroleptics with an anticholinergic action, hyperexcitation states or delirium may occur, as well as attacks of glaucoma. Tricyclic antidepressants should not be employed in combination with anti-arrhythmic agents of the quinidine type. Since clomipramine may diminish or abolish the antihypertensive effects of guanethidine, clonidine, reserpine, methyldopa, patients requiring concomitant treatment for hypertension should be given antihypertensives of a different type (e.g. diuretics, beta-blockers). Clomipramine may potentiate the cardiovascular effects of noradrenaline or adrenaline, amphetamine, as well as nasal drops and local anesthetics containing sympathomimetics. Methylphenidate and fluoxetine may increase the activity and plasma concentrations of tricyclic antidepressants. Caution should be exercised if clomipramine is administered together with cimetidine since cimetidine has been shown to inhibit the metabolism of several tricyclic antidepressants and clinically significant increases in plasma levels of clomipramine may occur. Taken from http://prozactruth.com/clomipramine.htm Substances which activate the hepatic mono-oxygenase enzyme system (e.g. barbiturates, phenytoin, nicotine) may lower plasma concentrations of tricyclic antidepressants and so reduce their antidepressive effects. Clomipramine should not be administered for a period of at least 14 days after the discontinuation of treatment with MAO-inhibitors due to the potential for severe interactions (see Contraindications). The same caution should also be observed when administering an MAO-inhibitor after previous treatment with clomipramine. Clomipramine should be discontinued prior to elective surgery, for as long as clinically feasible, since little is known about the interaction between clomipramine and general anesthetics. Concomitant administration of clomipramine and phenytoin may lead to elevated serum phenytoin concentration. If necessary, the phenytoin dosage should be adjusted accordingly. Neuroleptic agents (e.g. phenothiazines and butyrophenones) may increase the plasma concentration of clomipramine. No such effects are known to occur in combination with diazepam but it might be necessary to lower the dosage of clomipramine if administered concomitantly with alprazolam or disulfiram. If administered concomitantly with estrogens, the dose of clomipramine should be reduced since steroid hormones inhibit the metabolism of clomipramine. Because clomipramine is highly bound to serum proteins, the administration of clomipramine to patients taking other drugs that are highly bound to protein (i.e. warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects. Conversely, adverse reactions may result from the displacement of protein bound clomipramine by other highly bound drugs. Teratology: No teratogenic effects were observed in rats and mice at doses up to 20 times the maximum daily human dose. Slight nonspecific fetotoxic effects were seen in the offspring of pregnant mice given doses 10 times the maximum daily human dose. Slight nonspecific embryotoxicity was observed in rats given doses 5 to 10 times the maximum daily human dose. Animal Toxicology: As with tricyclic compounds, clomipramine has been associated with changes in testicular and lung tissue in long-term animal toxicology studies. In 1 and 2 year studies in rats, a dose 4 times the maximum daily human dose was associated with phospholipidosis in the lungs and changes in the testes (atrophy, aspermatogenesis, and calcification). In a 1 year toxicity study in dogs, testicular atrophy was detected in animals receiving 10 times the maximum recommended daily human dose. Adverse Effects
The most commonly observed adverse events associated with the use of clomipramine and not seen at an equivalent incidence among placebo-treated patients were gastrointestinal complaints, including dry mouth, constipation, nausea, dyspepsia, and anorexia; nervous system complaints, including somnolence, tremor, dizziness, nervousness and myoclonus; genitourinary complaints including changed libido, ejaculatory failure, impotence and micturition disorder; and other miscellaneous complaints, including fatigue, sweating, increased appetite, weight gain, and visual changes. Taken from http://prozactruth.com/clomipramine.htm The tabulations that follow list adverse reactions that have also been observed with clomipramine; these are categorized by organ system and listed in order of decreasing frequency. Neurological: Extrapyramidal effects such as ataxia, also headache, delirium, speech disorders, muscle weakness, muscle hypertonia, tinnitus, paresthesias of the extremities, convulsions, EEG changes, hyperpyrexia. Peripheral neuropathy has been reported with other tricyclic antidepressants. Behavioral: Drowsiness, fatigue, restlessness, confusion accompanied by disorientation (particularly in geriatric patients and patients suffering from Parkinson's disease), anxiety states, agitation, sleep disturbances, insomnia, nightmares, aggravated depression, hypomania or manic episodes, disturbed concentration, visual hallucinations, impaired memory, aggressiveness, yawning, depersonalization, activation of latent psychosis, delusions. Autonomic: Difficulty with accommodation, slurred speech, urinary retention, hot flushes, mydriasis, glaucoma, paralytic ileus. Cardiovascular: Hypotension, particularly orthostatic hypotension with associated vertigo, sinus tachycardia, palpitations. A quinidine-like effect and other reversible ECG changes in patients with normal cardiac status (such as flattening or inversion of T-waves, depressed S-T segments). Arrhythmias, hypertension, conduction disorders (e.g. widening of QRS complex, PQ changes, bundle-branch block), syncope. Fibrillation, myocardial infarction, stroke and unexpected death in patients with cardiovascular disorders have been reported with tricyclic antidepressants. Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, eosinophilia and purpura. One case of pancytopenia has been reported. Gastrointestinal: Vomiting, abdominal pain, diarrhea, taste perversion, elevated transaminases, obstructive jaundice, hepatitis with or without jaundice. Endocrine: Weight loss, breast enlargement and galactorrhea in the female, inappropriate antidiuretic hormone (ADH) secretion syndrome, gynecomastia in the male, changes in blood sugar levels, increase in prolactin levels, menstrual irregularity. Allergic or Toxic: Allergic skin reactions (skin rash, urticaria), photosensitization, pruritus, edema, drug fever. Withdrawal Symptoms: Abrupt cessation of treatment with tricyclic antidepressants after prolonged administration may occasionally produce nausea, vomiting, abdominal pain, diarrhea, insomnia, nervousness, anxiety, headache and malaise. These symptoms are not indicative of addiction.

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Education and Teaching Teaching EBP: “Getting from Zero to One.” Moving from Recognizing and Admitting Uncertainties to Asking Searchable, Answerable Questions Linda Johnston, RN, PhD, Ellen Fineout-Overholt, RN, PhD O urfirstcolumnintroducedreaderstotheemergenceof whoattendedthe2003conference“Signpostingthefuture new research-related content in nursing and medicalof EBHC (eviden

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Nonlinear Analysis 63 (2005) e1607 – e1617Non-linear strain theory for low-dimensionalB. Lassena , ∗, R. Melnika, M. Willatzena, L.C. Lew Yan Voonba Mads Clausen Institute for Product Innovation, University of Southern Denmark, Grundtvigs Allé 150, DK-6400 S Z nderborg, Denmark b Department of Physics, Worcester Polytechnic Institute, 100 Institute Road, Worcester, MA 01609, USA

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