Isolation from rat brain of a metabolic product, desmethylimipramine, that mediates the antidepressant activity of imipramine (Tofranil)

Gillette, James R.; Dingell, James V.; Sulser, Fridolin; Kuntzman, R.; Brodie, Bernard B.

doi:10.1007/bf02157980

Cited by 113 publications

(15 citation statements)

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“…In contrast to the APAP study is some recent work by G illette [18] with imipramine, a drug which counteracts primary depression in man and reverses the effects of reserpine. These workers found a complete lack of correlation between mouse brain levels of drug and pharmacologic ac tivity; onset of activity was delayed considerably beyond the time of oc currence of peak concentration of imipramine in the brain.…”

Section: Of Certain Biopharmaceutic and Pharmacodynamic Parametersmentioning

confidence: 85%

Measurement and Interpretation of Certain Biopharmaceutic and Pharmacodynamic Parameters

Gibaldi¹

1968

Chemotherapy

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Section: Of Certain Biopharmaceutic and Pharmacodynamic Parametersmentioning

confidence: 85%

Measurement and Interpretation of Certain Biopharmaceutic and Pharmacodynamic Parameters

Gibaldi¹

1968

Chemotherapy

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“…Thus, prior administration of imipramine and desmethylimipramine prevented many behavioural effects of reserpine or benzoquinolizines, including sedation and reduced locomotor activity (DOMENJOZ and THEOBALD, 1959;COSTA et al, 1960 b;GILLETTE et al, 1961;MAXWELL and PALMER, 1961;GARATTINI et al, 1962;SULSER et al, 1962;WILSON and TIsLOw, 1962;ASKEW, 1963;HALLIWELL et al, 1964) but did not prevent depletion of cerebral monoamines by reserpine (GARATTINI et al, 1962) although the rate of depletion of noradrenaline was slowed (MANARA et al, 1966). Rapid depletion was essential for prevention of reserpine effects since these were not found in cats, because of slow monoamine release following reserpine, nor in rats following repeated administration of small doses of reserpine (SULSER et al, 1964).…”

Section: B) Behaviour Temperature and Electrocortical Activitymentioning

confidence: 94%

Central Actions of Catecholamines

Marley¹,

Stephenson²

1972

Catecholamines

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“…Accordingly, James Dingell and I found that the anti-reserpine action of imipramine, discovered by Fridolin Sulser (67), was due to its demethylated metabolite, desipramine, (68) and that species differences in the anti-reserpine action were due to differences in the relative rates of formation and elimination of desipramine (69). In addition, Folke Sjoqvist et al (70) found that desipramine exerted its ''anti-tremorine'' effect by inhibiting the conversion of tremorine to oxotremorine, its active metabolite, but desipramine actually prolonged the action of oxotremorine by inhibiting its metabolism.…”

Section: Pharmacokinetics Of Parent Drugsmentioning

confidence: 98%

Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, NIH: A Short History

Gillette¹

2000

Annu. Rev. Pharmacol. Toxicol.

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Two analogs of phenylbutazone, labelled G-25671 and 6-28315, have been shown to have potent uricosuric effects. This report concerns the therapeutic properties in 44 patients of 6-28315, which is a sulfoxide metabolite of G-25671. AI-though the effects of this agent compared favorably with probenecid, the periods of administration were not sufficiently long to exclude toxicity. Duo analogos de phenylbutazona, iden-tificate como G-25671 e G-28315, se ha monstrate potente como agentes uricosuric. Le presente reporto con-ceme le proprietates therapeutic de G-28315 (un metabolito sulfoxydic de G-25671), observate in essayos con 44 patientes. Ben que le effectos esseva comparabile a illos de probenecido, le cursos de administration non esseva satis extense pro excluder toxicitate. HE PLACE of probenecid as a uricosuric agent suitable for protracted T use in the prevention and treatment of chronic gouty arthritis is now well established. There are, however, limitations to its effectiveness. Occasionally probenecid is not well tolerated and cannot be administered in effective dosage unless prior "desensitization" is possible; in our series drug rash occurred in 5 per cent and marked gastric distress in 8 per cent of 169 cases,l necessitating discontinuance of the drug in some instances. Probenecid has no "antirheu-matic" properties, hence does not relieve multiple joint stiffness and persistent joint pain associated with chronic gouty arthritis for the months required to mobilize urate depoists sufficiently. Even in daily dosage of two or three Gm., probenecid may fail to lower the serum urate to satisfactory levels, notably in patients with distinct renal damage. In our experience' the serum urate could not be maintained below 7 mg. per cent in 27 per cent of 186 protracted trials in 122 gouty subjects. In view of these limitations it would be desirable, at least in the speciaI circumstances indicated, to have alternative potent uricosuric drugs at hand. Of such drugs presently available, four have received special consideration: salicylate,2-5 zoxaz~larnine~~~ and the phenylbutazone analogs, G-25671 and the sulfoxide metabolite of G-25671, namely G-28315.A-1' The present communication is concerned with G-2831s (4-[phenylsulfoxyethyl]-l,2-diphenyl-3, 5-pyrazolidinedione) * and the results of its use in 44 gouty subjects.

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Isolation from rat brain of a metabolic product, desmethylimipramine, that mediates the antidepressant activity of imipramine (Tofranil)

Cited by 113 publications

References 1 publication

Measurement and Interpretation of Certain Biopharmaceutic and Pharmacodynamic Parameters

Measurement and Interpretation of Certain Biopharmaceutic and Pharmacodynamic Parameters

Central Actions of Catecholamines

Laboratory of Chemical Pharmacology, National Heart, Lung, and Blood Institute, NIH: A Short History

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