Erhöhte gehirn‐affinität von <sup>131</sup>J‐markierten n‐(alkyl)‐amphetaminen nach deuterierung

Wenzel, Martin

doi:10.1002/jlcr.2580271006

Cited by 12 publications

(6 citation statements)

References 15 publications

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“…Sometimes changed properties are due to different transport or penetration of the drug itself. Wenzel (1989) showed that deuterated amphetamines (also labelled with 131 I) were taken up more readily into mouse and rat brains than the hydrogenated forms of the same compounds. More often, changes in pharmacological action seem due to changes in drug metabolism.…”

Section: Properties and Uses Of Deuterated Drugsmentioning

confidence: 99%

Pharmacological uses and perspectives of heavy water and deuterated compounds

Kushner¹,

Baker²,

Dunstall³

1999

Can. J. Physiol. Pharmacol.

258

177

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Since the discovery of D20 (heavy water) and its use as a moderator in nuclear reactors, its biological effects have been extensively, although seldom deeply, studied. This article reviews these effects on whole animals, animal cells, and microorganisms. Both "solvent isotope effects," those due to the special properties of D20 as a solvent, and "deuterium isotope effects" (DIE), which result when D replaces H in many biological molecules, are considered. The low toxicity of D20 toward mammals is reflected in its widespread use for measuring water spaces in humans and other animals. Higher concentrations (usually >20% of body weight) can be toxic to animals and animal cells. Effects on the nervous system and the liver and on formation of different blood cells have been noted. At the cellular level, D20 may affect mitosis and membrane function. Protozoa are able to withstand up to 70% D20. Algae and bacteria can adapt to grow in 100% D2O and can serve as sources of a large number of deuterated molecules. D2O increases heat stability of macromolecules but may decrease cellular heat stability, possibly as a result of inhibition of chaperonin formation. High D2O concentrations can reduce salt- and ethanol-induced hypertension in rats and protect mice from gamma irradation. Such concentrations are also used in boron neutron capture therapy to increase neutron penetration to boron compounds bound to malignant cells. D2O is more toxic to malignant than normal animal cells, but at concentrations too high for regular therapeutic use. D2O and deuterated drugs are widely used in studies of metabolism of drugs and toxic substances in humans and other animals. The deuterated forms of drugs often have different actions than the protonated forms. Some deuterated drugs show different transport processes. Most are more resistant to metabolic changes, especially those changes mediated by cytochrome P450 systems. Deuteration may also change the pathway of drug metabolism (metabolic switching). Changed metabolism may lead to increased duration of action and lower toxicity. It may also lead to lower activity, if the drug is normally changed to the active form in vivo. Deuteration can also lower the genotoxicity of the anticancer drug tamoxifen and other compounds. Deuteration increases effectiveness of long-chain fatty acids and fluoro-D-phenylalanine by preventing their breakdown by target microorganisms. A few deuterated antibiotics have been prepared, and their antimicrobial activity was found to be little changed. Their action on resistant bacteria has not been studied, but there is no reason to believe that they would be more effective against such bacteria. Insect resistance to insecticides is very often due to insecticide destruction through the cytochrome P450 system. Deuterated insecticides might well be more effective against resistant insects, but this potentially valuable possibility has not yet been studied.

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Section: Properties and Uses Of Deuterated Drugsmentioning

confidence: 99%

Pharmacological uses and perspectives of heavy water and deuterated compounds

Kushner¹,

Baker²,

Dunstall³

1999

Can. J. Physiol. Pharmacol.

258

177

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“…Thus the penetration of sildenafil into tissue may be influenced by deuteration. Wenzel et al showed that deuterated amphetamines were taken up more readily into mouse and rat brains than the non-deuterated forms of the same compound [22].…”

Section: Discussionmentioning

confidence: 99%

Changed Phosphodiesterase Selectivity and Enhanced in vitro Efficacy by Selective Deuteration of Sildenafil

Schneider¹,

Mattern-Dogru²,

Hillgenberg³

et al. 2011

Arzneimittelforschung

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In order to explore whether selective deuteration of sildenafil affects selectivity and efficacy of the drug, the inhibitory activity of sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl-sulfonyl] -4-methylpiperazine citrate, CAS 139755-83-2) and three deuterated sildenafil derivatives, D8-piperazine-sildenafil (BDD-10402), D3-methyl-D8-piperazine-sildenafil (BDD-10403) and D5-ethoxy-Sildenafil (BDD-10406) against phosphodiesterases 1-6 was compared. Furthermore, the relaxant effect of sildenafil and its deuterated derivatives in a contractility assay on rabbit corpus cavernosum strips from New Zealand rabbits was investigated. BDD-10406 exhibits a 2-fold higher selectivity for phosphodiesterase 5 versus phosphodiesterase 6 than sildenafil. BDD-10406 and sildenafil inhibited cGMP formation with IC50 values of 6 nmol/L and 9 nmol/L, respectively. The corresponding IC80 values for BDD-10406 and Sildenafil were 33 nmol/L and 40 nmol/L, respectively. Sildenafil, BDD-10402, BDD-10403 and BDD-10406 relaxed the rabbit corpus cavernosum strips in a dose-dependent manner with ED50 values of 245 nmol/L, 91 nmol/L, 121 nmol/L and 85 nmol/L, respectively. Deuteration of sildenafil on the ethoxy group (BDD-10406) leads to enhanced selectivity for phosphodiesterase 5 versus phosphodiesterase 6 and higher efficacy in vitro. This is the first example of a deuteration effect on the inhibitory activity of a reversible enzyme inhibitor.

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“…The presence of 95% D 2 O was found to be equivalent to a 4-5°C reduction in storage temperature relative to H 2 O, and for macromolecular pharmaceuticals such as vaccines, as little as 7-25% D 2 O helps prevent protein denaturation. D 2 O medium has been recommended for storing organs, tissues, tissue parts, proteins or enzymes, sera and blood preparations for the perfusion of organs intended for transplants [72], micro organisms and enzymes [202], and hydrolyzable compositions such as a-hydroxy-carboxylic acids (especially benactyzine) [203]. Heavy water is also cryoprotective and may shield erythrocytes and other cells, cell constituents, organ parts or organs against damage by low-temperature (-26°C) storage [204].…”

Section: Applications Of D 2 O In Biological Systemsmentioning

confidence: 99%

“…Of special interest are drugs whose therapeutic properties are changed by deuteration. These include amphetamines, which are more readily transported into the brain in the deuterated form [72]; halogenated anaesthetics, such as selvoflurane, which when deuterated are no longer oxidized to toxic forms within the body [110]; and certain antimicrobial compounds like long-chain fatty acids [207] and d-fluorophenylalanine [208], whose deuterated forms are not oxidized by the affected microorganism and hence are toxic for longer periods of time. The role of deuterium in such multifaceted and diverse areas prompts us to consider increasing the use of heavy water in biological applications.…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

Role of heavy water in biological sciences with an emphasis on thermostabilization of vaccines

Balamurugan¹,

Rajak²,

Chakravarti³

et al. 2009

Expert Review of Vaccines

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Preservation of vaccines, viruses and other biologicals is one of the onerous tasks in maintaining the quality of the products from manufacture until they reach the end users. Live-attenuated viral vaccines, serum immunoglobulins, plasma fractions and clinical samples, including tissues and body fluids, are all materials that usually require cold-chain maintenance during storage and distribution. A number of stabilizers are currently used to help retain the quality of these materials, in particular vaccines, during transit. Deuterium oxide (heavy water; D(2)O) has previously been reported to have a protective effect on biomolecules (proteins and nucleic acids), cells and simple multicellular organisms against thermal shock. Of late, the potential of D(2)O has been demonstrated in stabilization of the oral polio and yellow fever 17D vaccines. This review is the outcome of a thorough search and scan of the literature in a quest to explore the potential use of heavy water in the stabilization of veterinary biologicals. The literature search revealed this potential of heavy water as exemplified by successful stabilization of oral polio and yellow fever vaccines. Through this review, the authors wish to inform animal health researchers and disseminate their knowledge on the use of heavy water in biomolecule stabilization and its potential application in the stabilization of veterinary vaccines and other biologicals.

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Erhöhte gehirn‐affinität von ¹³¹J‐markierten n‐(alkyl)‐amphetaminen nach deuterierung

Cited by 12 publications

References 15 publications

Pharmacological uses and perspectives of heavy water and deuterated compounds

Pharmacological uses and perspectives of heavy water and deuterated compounds

Changed Phosphodiesterase Selectivity and Enhanced in vitro Efficacy by Selective Deuteration of Sildenafil

Role of heavy water in biological sciences with an emphasis on thermostabilization of vaccines

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Erhöhte gehirn‐affinität von 131J‐markierten n‐(alkyl)‐amphetaminen nach deuterierung

Cited by 12 publications

References 15 publications

Pharmacological uses and perspectives of heavy water and deuterated compounds

Pharmacological uses and perspectives of heavy water and deuterated compounds

Changed Phosphodiesterase Selectivity and Enhanced in vitro Efficacy by Selective Deuteration of Sildenafil

Role of heavy water in biological sciences with an emphasis on thermostabilization of vaccines

Contact Info

Product

Resources

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Erhöhte gehirn‐affinität von ¹³¹J‐markierten n‐(alkyl)‐amphetaminen nach deuterierung