Penetration of Penethamate, a Penicillin Ester, into the Tissues of the Eye

Bleeker, G. M.; Maas, Evelien

doi:10.1001/archopht.1958.00940081033006

Cited by 20 publications

(6 citation statements)

References 6 publications

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“…As described previously, 10 synthesis of the N,N ‐dimethylaminoethylester (or DIMAEB; previously also termed “BUM5” or “STS5”) was initiated by penethamate, the diethylaminoethyl ester prodrug of benzylpenicillin that results in enhanced tissue distribution of this highly ionized antibiotic 24 . Synthesis of DIMAEB was based on our previous description 10 and performed as described in the following.…”

Section: Methodsmentioning

confidence: 99%

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain—A new treatment strategy for neonatal seizures?

Theilmann¹,

Brandt²,

Bohnhorst

et al. 2020

Epilepsia

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ObjectivesThe loop diuretic bumetanide has been proposed previously as an adjunct treatment for neonatal seizures because bumetanide is thought to potentiate the action of γ‐aminobutyric acid (GABA)ergic drugs such as phenobarbital by preventing abnormal intracellular accumulation of chloride and the subsequent "GABA shift." However, a clinical trial in neonates failed to demonstrate such a synergistic effect of bumetanide, most likely because this drug only poorly penetrates into the brain. This prompted us to develop lipophilic prodrugs of bumetanide, such as the N,N‐dimethylaminoethyl ester of bumetanide (DIMAEB), which rapidly enter the brain where they are hydrolyzed by esterases to the parent compound, as demonstrated previously by us in adult rodents. However, it is not known whether esterase activity in neonates is sufficient to hydrolyze ester prodrugs such as DIMAEB.MethodsIn the present study, we examined whether esterases in neonatal serum of healthy term infants are capable of hydrolyzing DIMAEB to bumetanide and whether this activity is different from the serum of adults. Furthermore, to extrapolate the findings to brain tissue, we performed experiments with brain tissue and serum of neonatal and adult rats.ResultsSerum from 1‐ to 2‐day‐old infants was capable of hydrolyzing DIMAEB to bumetanide at a rate similar to that of serum from adult individuals. Similarly, serum and brain tissue of neonatal rats rapidly hydrolyzed DIMAEB to bumetanide.SignificanceThese data provide a prerequisite for further evaluating the potential of bumetanide prodrugs as add‐on therapy to phenobarbital and other antiseizure drugs as a new strategy for improving pharmacotherapy of neonatal seizures.

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Section: Methodsmentioning

confidence: 99%

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain—A new treatment strategy for neonatal seizures?

Theilmann¹,

Brandt²,

Bohnhorst

et al. 2020

Epilepsia

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“…An early example of such a material was penethamate, an ester of penicillin which is hydrolyzed in vivo. This was found, in rabbits, to penetrate the vitreous body readily from the blood, whereas penicillin does not (BLEEKER and MAAs 1958).…”

Section: B) Prodrugsmentioning

confidence: 98%

Ocular Pharmacokinetics

Maurice¹,

Mishima²

1984

Pharmacology of the Eye

217

169

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“…Blecker and Maas [23] compared two peni cillins, one a diethylamino-ethyl-ester, strongly liposoluble, and the other procaine-penicillin, weakly liposoluble. The experiments have shown that the diethylamino-ester is found in greater concentra tions in the aqueous humor.…”

Section: Discussionmentioning

confidence: 99%

The Penetration of Vibramycin (Doxycycline) in Human Aqueous Humor

Tsacopoulos¹

1969

Ophthalmologica

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Penetration of Penethamate, a Penicillin Ester, into the Tissues of the Eye

Cited by 20 publications

References 6 publications

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain—A new treatment strategy for neonatal seizures?

Hydrolytic biotransformation of the bumetanide ester prodrug DIMAEB to bumetanide by esterases in neonatal human and rat serum and neonatal rat brain—A new treatment strategy for neonatal seizures?

Ocular Pharmacokinetics

The Penetration of Vibramycin (Doxycycline) in Human Aqueous Humor

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