Phenytoin Prodrugs III: Water-Soluble Prodrugs for Oral and/or Parenteral Use

Varia, Sailesh A.; Schuller, S.; Sloan, Kenneth B.; Stella, Valentino J.

doi:10.1002/jps.2600730812

Cited by 101 publications

(26 citation statements)

References 41 publications

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“…This is consistent with previous findings that ACC-9653 is quantitatively converted to phenytoin in vitro (Quon and Stampfli, 1987) and in vivo (Rivenburg et al, 1987) in humans, and in dogs (Lai et al, 1987) and rats (Varia and Stella, 1984~). The conversion halflife is -8 min in volunteers, -3 min in dogs, and < 1 min in rats.…”

Section: Discussionsupporting

confidence: 92%

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

et al. 1989

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ACC-9653, the disodium phosphate ester of 3-hydroxymethyl-5,5-diphenylhydantoin, is a prodrug of phenytoin with advantageous physicochemical properties. ACC-9653 is rapidly converted enzymatically to phenytoin in vivo. ACC-9653 and phenytoin sodium have equivalent anticonvulsant activity against seizures induced by maximal electroshock (MES) in mice following i.p., oral, or i.v. administration. The ED50 doses were 16 mg/kg for i.v. ACC-9653 and 8 mg/kg for i.v. phenytoin sodium. ACC-9653 and phenytoin sodium have similar antiarrhythmic activity against ouabain-induced ventricular tachycardia in anesthetized dogs. The total doses of ACC-9653 or phenytoin sodium necessary to convert the arrhythmia to a normal sinus rhythm were 24 +/- 6 and 14 +/- 3 mg/kg, respectively. Only phenytoin sodium displayed in vitro antiarrhythmic activity against strophanthidin-induced arrhythmias in guinea pig right atria. In anesthetized dogs, a high dose of ACC-9653 (31 mg/kg) was infused over 15, 20, and 30 min and the responses were compared to an equimolar dose of phenytoin sodium (21 mg/kg). The ACC-9653 and phenytoin sodium treatments produced similar marked reductions in diastolic blood pressure and contractile force (LVdP/dt). The maximum effects of each treatment occurred at the time of maximum phenytoin sodium levels. Acute toxicity studies of ACC-9653 and phenytoin sodium were carried out in mice, rats, rabbits, and dogs by i.v., i.m., and i.p. routes of administration. The systemic toxic signs of both agents were similar and occurred at approximately equivalent doses. Importantly, the local irritation of ACC-9653 was markedly less than phenytoin sodium following i.m. administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 92%

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

et al. 1989

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“…Professor Stella has taken an innovative but practical approach to prodrug design, where he first identifies a critical issue in pharmaceutical sciences and medicinal chemistry, and then searches for a prodrug to overcome the problem. Professor Stella's work on development of fosphenytoin (Cerebyx®) was highly innovative and ground‐breaking 15,16. The application of a phosphoryloxymethyl promoiety allowed the development of a highly water‐soluble prodrug of phenytoin 16.…”

Section: Fields Of Researchmentioning

confidence: 99%

Effects of supportive‐expressive group therapy on survival of patients with metastatic breast cancer: A randomized prospective trial

Kissane¹,

Li²

2007

Cancer

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B ased on a very small subsample of 25 estrogen receptor (ER)-negative women with breast cancer, 13 of whom received group therapy, Spiegel et al. 1 conducted an exploratory analysis that found increased survival for these women. They have argued that these women were not protected by hormonal therapies.In our much larger Australian study of group therapy with women with advanced breast cancer, there were 70 ER-negative women. 2 Kaplan-Meier survival analysis showed no difference between the 43 hormone receptor-negative (estrogen) patients in the group intervention condition and the 27 hormone receptor-negative patients in the control condition. The median survival durations were at 15.5 months (95% confidence interval [CI], 9.5-25.8) for patients in the intervention condition and 17.2 months (95% CI, 8.1-26.5) for patients in the control condition, respectively. The logrank test for equality of survivor functions was not statistically significant (chi-square (2) ¼ 0.55, P ¼ .46).We also tried to replicate their analytic method exactly. In a Cox proportional hazards model we tested the effect of a treatment by positive hormone receptor status interaction, after controlling for intervention site, intervention site by treatment interaction, a treatment main effect, and a positive hormone receptor status main effect. We also centered the predictors as recommended in Kraemer and Blasey, 3 with coding of 1/2 and À1/2 in dichotomous variables (for both the randomization and hormone receptor status variables) and 1-1/m and À1/m for the site dummy variables (where m ¼ 5 in our study). Again, the result was consistent with the Kaplan-Meier survival analysis. There was no hormone receptor status by treatment interaction (Cox proportional hazards B ¼ 1.14, Wald statistic ¼ 0.38, P ¼ .71).Given our inability to replicate their latest exploratory finding, we conclude that it is a chance finding. Women should not be swayed into false hope, but appreciate that strong evidence has emerged that group therapy does not prolong survival. Group therapy does prevent depression and improve quality of life, thus representing a wonderful adjunctive psychosocial treatment for those with cancer. REFERENCES

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“…MaterialssFosphenytoin, isolated as its dihydrate, was synthesized according to the method developed by Varia et al 15 The final material, as a 80.6 mg/mL aqueous solution contained about 20 µg/mL of phenytoin as an impurity. The synthesis and characterization procedures for (SBE)7m--CD have been described elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Increased Shelf-Life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7M-β-CD

Narisawa¹,

Stella²

1998

Journal of Pharmaceutical Sciences

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Fosphenytoin, a water-soluble prodrug of phenytoin, degrades primarily to phenytoin at pH values <8 during long term storage; phenytoin readily precipitates when formed from fosphenytoin due to its limited aqueous solubility. The objective of this study was to develop stable formulations of fosphenytoin in the pH range of 7.4-8. 0 by inhibiting the phenytoin precipitation through complexation with a parenterally safe cyclodextrin, (SBE)7m-beta-CD. Phase solubility studies at 25 degreesC revealed that phenytoin could be effectively solubilized by (SBE)7m-beta-CD both in the presence and absence of 80.6 mg/mL fosphenytoin (as its dihydrate). The binding constants for the phenytoin/cyclodextrin complex were found to be 1073 and 792 M-1 at pH 7.4 and pH 8.0, respectively. Because of the competitive inclusion between fosphenytoin and phenytoin with (SBE)7m-beta-CD, the extent of solubilization of phenytoin was lower, as expected, in the presence of fosphenytoin than in the absence of fosphenytoin, even though the binding constants for the fosphenytoin/cyclodextrin complex were relatively small (41-45 M-1). Initial rates were used to follow the production of phenytoin from fosphenytoin. Zero-order kinetics were observed under all conditions investigated. Phenytoin production rates were followed at 25, 37, and 50 degreesC in the presence of 0.03 or 0.06 M (SBE)7m-beta-CD. It was projected from the solubility of phenytoin and the kinetic information that fosphenytoin shelf lives as high as nine years at 25 degreesC and pH 7.4 in the presence of 60 mM of (SBE)7m-beta-CD might be possible while longer shelf lives might be possible at pH 8.

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Phenytoin Prodrugs III: Water-Soluble Prodrugs for Oral and/or Parenteral Use

Cited by 101 publications

References 41 publications

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

Pharmacology of ACC‐9653 (Phenytoin Prodrug)

Effects of supportive‐expressive group therapy on survival of patients with metastatic breast cancer: A randomized prospective trial

Increased Shelf-Life of Fosphenytoin: Solubilization of a Degradant, Phenytoin, through Complexation with (SBE)7M-β-CD

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