Diabetes insipidus treatment dog. The Q–T interval and the Mellaril story: a cautionary tale
This produced a small controversy in the s that had a major impact on patient care.
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Inthe Novartis Company cautioned physicians about further use of the antipsychotic drug Mellaril thioridazine. The company announced that the drug can entail dangerous cardiac complications. This information was already known in the mids, and not only did Sandoz one of the predecessor companies of Novartis ignore it, they attempted to discount it at scientific meetings and disregarded the warnings of several clinical scientists.
- - Дай голосе слышалось.
- Acta Medica () | Arcanum Digitheca
The story is a textbook case of ignoring scientific warnings in favor of corporate interests. But was this good or bad? There was the benign repolarization school.
InM. But events were in the saddle, and galloped in a very different direction.
Some background: It happens quite frequently that drugs are withdrawn or new warnings of their side-effects are circulated. On July 31,Novartis Pharmaceuticals sent a letter to all physicians and pharmacists in Canada, warning that the use of the drug Mellaril should be significantly curtailed.
These warnings came more than thirty years too late.
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Here is how the controversy unfolded: InH. T-waves were flattened out and sometimes inverted, occasionally S—T segments became convex and new waves appeared. In that study, two fatal cases of arrhythmia occurred Kelly et al. Jean, The study had been completed inbut before it was published, the following incident occurred at Hôpital des Laurentides: A patient who had been receiving high mg per day doses of thioridazine over a period of ten weeks, suddenly became unconscious and passed into a state of shock.
It happened that there were two physicians in the room, one of them a cardiologist. An ECG demonstrated ventricular tachycardia.
It was noted that a prior ECG of the patient, six weeks after the initiation of thioridazine therapy, had shown bradycardia and prolongation of the QT Desautels et al. These findings led Ban and co-workers to conduct a survey to determine the incidence of cardiac conductance changes with thioridazine.
It was clear that such complications existed, but what was the size of the problem? Of the 92 patients receiving drugs other than thioridazine, 12, or 13 percent, displayed an abnormal ECG. Seventeen, or In or Ban travelled to Basel to report these findings to Sandoz and met with the president and head of pharmacology of the firm Ban TA, personal communication to E Shorter, 11 Mar Of the 55 patients they studied, 44 percent developed abnormal electrocardiograms.
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Most of the changes were concerned with the T-wave. They appeared at all dose levels from to mg per day Graupner and Murphree, In organizing the symposium, Ban wanted to ensure that a fair picture of Mellaril was offered.
Всем известно, чего угодно, чему клонит.
He had mentioned the meeting to Sandoz, and the company paid the travel cost for Wendkos to attend Ban, Here is where events took over. Other investigators began learning of the cardiac dangers of diabetes insipidus treatment dog. And lo and behold, we did discover that a metabolite that is not psychoactive, sulforidazine, does have an adverse cardiovascular effect.
Gottschalk, who in the meantime had moved to the Irvine campus of the University of California, reported with co-workers the existence of this previously unknown metabolite of mesoridazine and thioridazine in Dinovo et al. Did Sandoz then become interested? Not really. I asked the head of the organic chemistry diabetes insipidus treatment dog at UCI whether she could manufacture it for me because I wanted to test the effects of the metabolite on cardiovascular function in dog experiments.
She could do it for a certain amount of money, but I never was able to diabetes insipidus treatment dog the necessary funds.
Gottschalk was not the only researcher to be brushed off by Sandoz. In Donald Gallant and co-workers at Tulane University reported a double-blind ECG comparison of thioridazine and thiothixene Dillenkoffer et al, We published that.
Acta Medica 17. (1961)
In fact, my cardiology fellow that read the EKGs could identify thioridazine, blind. After we published, somebody from Sandoz called and started yelling on the phone at me, criticizing me, saying I was unethical for publishing the data.
These early warnings did not prevent Sandoz from further marketing the preparation. And in George Simpson and co-workers at Rockland State Hospital found that it was precisely in the elderly that thioridazine prolonged QT intervals Branchey et al, While the Diabetes insipidus treatment dog studies showed that cardiac conductance changes appeared at daily dosages above mg.
For Sandoz — and its successor organization Novartis — it was irresponsible not to say reckless to have ignored such warnings for more than thirty years, putting the lives of many patients at risk.
The Q–T interval and the Mellaril story: a cautionary tale
The entire story of shortsightedly placing corporate interests ahead of science could be found in an MBA curriculum on how not to market a pharmaceutical preparation. References Ban TA. Psychopharmacology for the Aged.
Basel: Karger; Nashville: American College of Neuropsychopharmacology; Ban TA, St. Jean A, Desautels S. Amsterdam: Elsevier;p. Jean A. The effect of phenothiazines on the electrocardiogram. J Can Med Assoc ; — High- and low-potency neuroleptics in elderly psychiatric patients.
J Am Med Assoc ; —2. Desautels S, Filteau C, St. Ventricular tachycardia associated with administration of thioridazine hydrochloride Mellaril. J Can Med Assoc ; —1.
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Electrocardiographic evaluation of thiothixene: a 2-es típusú cukorbetegség folyékony magvak kezelése double-blind comparison with thioridazine. Adv Biochem Psychopharmacol ; 9: — Isolation of a possible new metabolite of thioridazine and mesoridazine from human plasma.
Res Commun Chem Pathol Pharmacol ; 7: — GLC analysis of thioridazine, mesoridazine, and their metabolites. J Pharma Sci ; —9.
Dis Nerv Syst ;40 8 through ; 41 11Mellaril advertisement 14 instances.
Description
Dis Nerv Syst ; 44 5—7Mellaril advertisement 3 instances. Electrocardiographic changes associated with the use of thioridazine. Thioridazine hydrochloride Mellaril : its effect on the electrocardiogram and a report of two fatalities diabetes insipidus treatment dog electrocardiographic abnormalities.
Acta Medica Margit-László, F. Each experiment lasted 5 hours. The value of creatinine, excreted during 5 hours, was given in mg per g body weight. We determined also the ratio Na:K.
Kingstone E. Montreal: Quebec Psychopharmacological Research Association;p. Novartis Pharmaceuticals Canada.
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Psychiatric News, August 18,p. Nashville: American College of Neuropsychopharmacology; —, Montreal: Quebec Psychopharmacological Research Association; — Wendkos MH. The significance of electrocardiographic changes produced by thioridazine. J New Drugs ; —
