Intravenous Injection of Thalidomide in Pregnant Rabbits

Fox, R. R.; Sawin, P. B.; Crary, D. D.; Wuest, H

doi:10.1126/science.153.3733.310

Cited by 9 publications

(3 citation statements)

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“…In a report in Science, entitled "Intravenous injection of thalidomide in pregnant rabbits" by Fox et al (1), the authors claimed to have produced a supersaturated solution of thalidomide (1 mg/ml) in a medium containing carboxyrnethylcellulose (CMC, 5 mg/ml) and glucose (50 mg/ml). In brief, their preparation was as follows: 0.5 g of CMC was heated with 100 ml of water until the mixture became a clear solution (about 10 minutes).…”

Section: Thalidomide Solutionsmentioning

confidence: 99%

Thalidomide Solutions

Schumacher¹,

Blake²,

Gillette³

et al. 1966

Science

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In a report in Science, entitled "Intravenous injection of thalidomide in pregnant rabbits" by Fox et al. (1), the authors claimed to have produced a supersaturated solution of thalidomide (1 mg/ml) in a medium containing carboxymethylcellulose (CMC, 5 mg/ml) and glucose (50 mg/ml). In brief, *their preparation was as follows: 0.5 g of CMC was heated with 100 ml of water until the mixture became a clear solution (about 10 minutes). Five grams of glucose was dissolved in the solution, and 100 mg of thalidomide was added. The mixture was then boiled until all of the thalidomide was dissolved (about 20 minutes). The solution was immediately filtered, cooled in a water bath to 500C, and then infused, at a temperature of about 40°C, into pregnant rabbits.Since thalidomide undergoes spontaneous hydrolysis in neutral and alkaline solutions even at room temperatures (2), the drug might be rapidly converted to its hydrolytic products under the conditions described by the authors. Using their method, we prepared solutions of tritiated thalidomide and then assayed them for thalidomide by a method developed in our laboratory. A portion of the solution was shaken with ten volumes of ethylene dichloride (EDC). Over 90 percent of the thalidomide, but less than 2 percent of the hydrolytic products, was extracted into the organic phase. Part of the extract was assayed for radioactivity in a liquid-scintillation spectrometer; another was subjected to radio-chromatography. Our results indicated that the amount of thalidomide in the solution after it cooled to 40°C ranged from 4.5 to 30 percent of the amount added. The variability depended on the vigorousness of boiling; intense boiling caused more hydrolysis than slow boiling did.The possibility that tritiated thalidomide is hydrolyzed more rapidly than the unlabeled compound does not seem likely, since virtually identical values for the amounts of unchanged thalidomide were obtained when the EDC extracts were assayed by both the radiochemical method and that of ultra violet spectroscopy of Green and Benson (3).Boiling the solution of CMC and glucose with thalidomide caused the pH to drop from an initial value of about 7.1 to a value of about 5.3, as the acidic metabolites were formed. Since hydrolysis of the drug proceeds more rapidly in neutral than in slightly acidic solutions, the presence of buffers would obviously influence the rate of hydrolysis. Carboxymethyl cellulose might have served as a weak buffer in the authors' medium, for this substance contains from 7 to 8.5 percent sodium (4). Indeed, when 100 ml of distilled water (pH 6.82) was boiled with 100 mg of thalidomide, only about 10 percent of the drug was hydrolyzed. Since

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Section: Thalidomide Solutionsmentioning

confidence: 99%

Thalidomide Solutions

Schumacher¹,

Blake²,

Gillette³

et al. 1966

Science

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“…Thus, many models of thalidomide action focus entirely on the limb but cannot explain other defects seen in thalidomide embryopathy. A number of animal embryo model systems have been used to study its actions, the most popular being chick,35–38 rabbit39, 40 and marmoset 41. Over 30 models/hypotheses have been postulated over the years 6, 19, 42.…”

Section: Introductionmentioning

confidence: 99%

Thalidomide‐induced limb defects: resolving a 50‐year‐old puzzle

2009

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Despite the recent discovery that thalidomide causes limb defects by targeting highly angiogenic, immature blood vessels, several challenges still remain and new ones have arisen. These include understanding the drug's species specificity, determining molecular target(s) in the endothelial cell, shedding light on the molecular basis of phocomelia and producing a form of the drug that is clinically effective without having side effects. Now that the trigger of thalidomide-induced teratogenesis has been uncovered, a framework is proposed, incorporating and uniting previous models of thalidomide action, explaining how thalidomide causes not just limb defects, but also all the other defects it induces.

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“…Nach Applikation von TWEEN-vermittelten waBrigen Aufschwemmungen von Thalidomid (4' 10-3 M) auf die Sprofsspitzen von Pisumund Impatiens-Pflanzen konnten wir (zusammen mit HAUSNER) zwar einige del' als Sekundar-Effekte del' PBA beschriebenen Transformationen im Bliitenbereich beobachten, abel' mehrmalige Versuchsserien mit Eranthis-Embryonen blieben ergebnislos. Das kann an del' Applikationsmethode liegen, da Thalidomid im Gegensatz zu PBA nicht wasserloslich ist, AuBerdem gibt es Literaturangaben(Fox et al 1966), nach den en Thalidomid beim Tier MiBbildungen del' Feten nul' nach oraler, nicht abel' nach parenteraler Applikation erzeugt, was darauf hindeuten konnte, daB ein Abbauprodukt das eigentlich wirksame Teratogen ist. Wir werden die Versuche unter Beriicksichtigung del' angedeuteten Problematik fortsetzen.…”

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Die phänokopierende Wirkung der Phenylborsäure

Haccius

1976

Berichte der Deutschen Botanischen Gesellschaft

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ZusammenfassungMit dem Ausdruck „Phänokopie” werden somatisch induzierte Aberrationen des Phänotyps bezeichnet, die das Manifestationsmuster eines veränderten Genotyps imitieren (bekanntestes, wenn auch nicht unumstrittenes Beispiel: Die Thalidomid‐induzierten Extremitäten‐Mißbildungen). Charakteristisch für phänokopierende Noxen ist ihre Phasenspezifität, d. h. sie sind nur wirksam, wenn sie eine eng begrenzte Entwicklungsstufe treffen (sensible Phase).Es wird an folgenden Beispielen gezeigt, daß eine richtig terminierte, einmalige Applikation geeignet dosierter Phenylborsäure‐Lösungen bei Höheren Pflanzen die Manifestationsmuster bekannter Mutationen hervorrufen kann und daß der Effekt streng phasenspezifisch ist. 1. Lanzettblättrigkeit der Tomate, 2. Choripetalie bei Nicotiana‐Arten, 3. A‐ und Oligo‐Petalie bei Arabidopsis thaliana und einer Reihe weiterer Dikotylen‐Arten, 4. Tripistillie und andere Blütenmißbildungen bei der Erbse.Das typische PBA‐Syndrom, nämlich von bloßer Separierung über Rudimentierung bis zum Total‐Ablast gehende Entwicklungsstörungen einzelner Blattorgane, ist bisher ausschließlich nach Anwendung von Aryl‐ und Arylenborsäuren beobachtet worden. Transformationen im Blütenbereich, wie Staminodie oder Pistillodie, werden als Sekundärphänomene erklärt (Freisetzung von Entwicklungspotenzen nach Ausfall benachbarter Organe). Sie können auch unter dem Einfluß anderer Noxen (einschließlich Thalidomid) auftreten.Es gibt zur Zeit noch keine einigermaßen stichhaltige Vorstellung über den teratogenen Wirkungsmechanismus der Phenylborsäure. Das gleiche gilt auch vom Thalidomid. Vielleicht könnte der an Pflanzen sicher und ohne Aufwand zu reproduzierende Phenylborsäure‐Effekt als Arbeitsmodell für eine Untersuchung der exogen induzierten Teratogenese dienen.

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Intravenous Injection of Thalidomide in Pregnant Rabbits

Cited by 9 publications

References 6 publications

Thalidomide Solutions

Thalidomide Solutions

Thalidomide‐induced limb defects: resolving a 50‐year‐old puzzle

Die phänokopierende Wirkung der Phenylborsäure

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