The effect of vehicle additives on the transdermal delivery of nitroglycerin.
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Administration, Cutaneous↗
Biomedical subjects
N Bodor
Publications and source records attributed to N Bodor.
Redox drug delivery systems for targeting drugs to the brain.
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Acyclovir↗
Improved delivery through biological membranes XXV. Enhanced and sustained delivery of trifluorothymidine to the brain using a dihydropyridine in equilibrium pyridinium salt type redox delivery system.
A series of alpha,alpha,alpha-trifluorothymidine (TFT) derivatives was designed and studied for brain-enhanced/specific delivery of this antiviral drug. The derivatives were esters involving one or both of TFT's hydroxy functions and N-methyl-dihydronicotinic acid. Such esters are subject to oxidative (to trigonelline) and hydrolytic metabolic transformations. Thymidine (T) was used as a model compound and the kinetics of the oxidative and hydrolytic conversion of some 16 derivatives of T and TFT were studied in various biological fluids. One compound, 3'-[O-(N-methyl-1,4-dihydronicotinoyl)]-5'-[O-(pivaloyl)]-TFT (14), was selected for in vivo studies. The compound appeared to cross the blood-brain barrier and to be converted in the brain by successive oxidative and hydrolytic processes to the 3'-[O-(N-methyl nicotinoyl)]TFT (17); this quaternary pyridinium salt was 'locked in' the brain and then further hydrolyzed in a sustained manner to release TFT, detected in measurable levels at least until 18 hours following the i.v. injection of 14. TFT was also identified as an in vitro degradation product in the different biological tissues and fluids. The results suggest that the dihydropyridine in equilibrium pyridinium salt redox delivery system can be successfully used for the brain delivery of antiviral agents that would not otherwise cross the blood-brain barrier.
Animals↗
Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1,4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU.
A redox chemical delivery system based on the NADH in equilibrium NAD+ model was applied to an active metabolite (D) of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), i.e. CCNU-OH. The 1,4-dihydrotrigonelline ester of CCNU-OH, N-(2-chloro ethyl)-N'-[trans-4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)cyc lohexyl]- N-nitrosourea (D-CDS) was prepared by a direct hydride transfer reaction of the corresponding pyridinium precursor (D-Q+) with a highly reactive 1-benzyl-1,2-dihydroisonicotinamide. The in vitro kinetics in biological fluids indicated facile oxidative conversion of D-CDS to D-Q+. An in vivo study showed that one intravenous injection to rats of D-CDS resulted in rapid brain accumulation of D-Q+, followed by a sustained release of CCNU-OH, while D-Q+ was rapidly eliminated from systemic circulation. The ratio of brain/blood concentration of D-Q+ was found to increase progressively with time. At an equimolar dose of CCNU-OH, the ratio of brain/blood concentration for CCNU-OH was found to be close to unity.
Animals↗
Potential treatment of herpes simplex virus encephalitis by brain-specific delivery of trifluorothymidine using a dihydropyridine in equilibrium pyridinium salt type redox delivery system.
A newly described, drug-carrier delivery system in which a lipophilic derivative is enzymatically converted to a hydrophilic compound was used to treat experimental herpes simplex virus (HSV) encephalitis. Because trifluorothymidine (TFT) does not cross the blood brain barrier, the lipophilic dihydropyridine derivative 3'-(N-methyl-1, 4-dihydronicotinoyl)-5-'pivaloyltrifluorothymidine (DHTFT) was synthesized and characterized by HPLC. After intravenous administration of 20 mg/kg of DHTFT to rats, the quaternary, intermediate compound 3'-N-methyl-1,4-nicotinoyltrifluorothymidine was measured at levels of 7-8 micrograms/g brain at 1 hour and 13.5 +/- 0.8 micrograms/g brain at 4 hours. This compound had antiviral activity equivalent to that of TFT against HSV-1 in a plaque reduction assay (ID 50 = 0.5-1.0 microgram/ml), either directly or by conversion to TFT. Although survival was not prolonged in a rat model of HSV encephalitis, a statistically significant reduction in titer of HSV/g brain was achieved with daily intravenous treatment with DHTFT. TFT was not detected in brains of rats at 1 and 4 hours after intravenous DHTFT, but a low level was observed at 18 hours, 0.3 +/- 0.05 microgram/g brain. These data suggest that the lipophilic compound DHTFT or a lipophilic metabolite crossed the blood brain barrier and was converted to a quaternary compound, which accumulated in the brain and which was either active directly or was converted to TFT. The drug-carrier delivery system described here can potentially be used in the treatment of HSV or other viral encephalitides.
Animals↗
Improved delivery through biological membranes XX: Nicotinamide----dihydronicotinamide based ester-linked redox carrier systems.
The 1-carboxyalkyl nicotinamide----dihydronicotinamide redox pair is a new type of brain-enhanced chemical delivery system for drugs containing hydroxyl groups. The rate of oxidation of the dihydro carrier form and subsequent "lock-in" into the brain of the quaternary carrier-drug species, as well as the rate of the hydrolytic release of the drug, depend on both the length and branching of the alkyl chain separating the carrier ring system. Testosterone was used as a model drug, and it was successfully released in a sustained and enhanced manner to the brain in significantly higher concentrations than with the previously reported trigonelline----dihydrotrigonelline carrier system.
Animals↗
Sustained brain-specific delivery of estradiol causes long-term suppression of luteinizing hormone secretion.
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Animals↗
Improved delivery through biological membranes. Synthesis, distribution, and neurochemical effects of a tryptamine chemical delivery system.
Enhanced central delivery of tryptamine was proposed by application of a dihydropyridine in equilibrium pyridinium salt redox system. This drug delivery method, which relies on biochemistry similar to that which occurs in the NAD+ in equilibrium NADH coenzyme system, required synthetic derivatization of tryptamine. When the resulting tryptamine chemical delivery system (TCDS) was systematically administered, it passed the blood-brain barrier intact and then oxidized. The resulting quaternary form (TQ+) accumulated in the brain of rats relative to most peripheral organs. The only organ in which a more rapid efflux was not demonstrated was the heart. Intestinal administration of the TCDS showed the ability of the system to undergo absorption and to survive the first pass through the liver. The TCDS caused central neurochemical changes consistent with central delivery of tryptamine. Possible applications of the TCDS are discussed.
Animals↗
Improved delivery through biological membranes XIX: Novel redox carriers for brain-specific chemical delivery systems.
New dihydropyridine in equilibrium pyridinium salt-type redox carrier systems were developed in which the drug is linked via the ring nitrogen atom of nicotinamide. The rate of oxidation of the dihydropyridine forms, and thus the overall and brain-specific distribution of the corresponding 3-carbamoyl-1-carbamoylalkyl-drug quaternary salts, depends on the number of methylene groups separating the ring nitrogen and the carbamoyl function linked to the drug.
Animals↗
Direct evidence for brain-specific release of dopamine from a redox delivery system.
Dopamine (1) was transformed into a lipoidal redox chemical delivery system which crosses the blood brain barrier and is converted to a quaternary ammonium precursor of 1, thus "locking in" this ionized moiety. Systemic administration of this chemical delivery system for 1 increased concentrations of the major acid metabolite of 1, dihydroxyphenylacetic acid, (6) in several brain regions, and despite sustained inhibition of prolactin secretion, concentrations of 1 were unchanged. Inhibition of monoamine oxidase did not encourage the formation of 1 from this delivery system. When de novo synthesis of 1 was inhibited, however, regional brain concentrations of both 1 and dihydroxyphenylacetic acid acid were increased by systemic administration of the delivery system. This study provides direct evidence for the brain-specific delivery of 1 by a redox chemical delivery system and indicates that the 1 formed is delivered to sites which normally store newly biosynthesized 1.
Animals↗
Targeting of drugs to the brain.
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Acetylcholinesterase↗
Improved delivery through biological membranes XIV: Brain-specific, sustained delivery of testosterone using a redox chemical delivery system.
The dihydropyridine in equilibrium pyridinium salt redox delivery system was used for the specific delivery and sustained release of testosterone in the brain. Administration of the N-methyl-1,4-dihydro nicotinate ester of testosterone in female rats gave high and sustained brain levels of the corresponding quaternary ester, testosterone trigonellinate. This contrasted with rapid elimination from the general circulation. Release of testosterone "locked into" brain as the quaternary salt was sustained, t1/2 = 20 h.
Animals↗
Formation of adrenaline in the iris-ciliary body from adrenalone diesters.
Many diesters of adrenalone have high ocular sympathomimetic activity although adrenalone itself, even if delivered intraocularly, is practically inactive. Thus these diesters cannot be considered pro-drugs of adrenalone, since adrenalone is not a drug. The mechanism of action of these adrenalone derivatives was studied on the selected, potent diisovaleryl adrenalone. It was found that adrenaline is formed from the diester, but not from adrenalone. While the inactive adrenalone is also formed hydrolytically and found in every compartment of the eye, the active epinephrine (adrenaline) was found only in the iris-ciliary body, as a result of a reduction-hydrolytic steps sequence. Thus the adrenalone diesters represent a type of site-specific delivery system for epinephrine.
Animals↗
A rapid, quantitative in vivo assay for narcotic antagonists.
Tail skin temperature (TST) response of morphine-dependent rats was evaluated as a potential in vivo assay for the activity of narcotic antagonists. Dependency was produced in rats by repeated subcutaneous implantation of morphine-containing pellets and TST was evaluated by thermistor probes attached to the dorsal surface of the tail. TST was determined prior to and following administration of either naloxone (NAL: 0, 0.01, 0.1, 0.5 or 1.0 mg/kg body weight); naltrexone (NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight); or 6-Desoxy-6-methylenenaltrexone (DM-NALT: 0.001, 0.005, 0.01, 0.02 or 0.1 mg/kg body weight). Each of the narcotic antagonists caused a dose-dependent increase in tail skin temperature in morphine dependent rats. The initial TST increase was observed by 5 minutes and the maximal TST response occurred 15 to 25 minutes after drug administration. For each drug evaluated, a linear relationship was observed between the dose and maximal change in TST and between the dose and the area under the TST response curve. Determination of ED50 for the TST response revealed the expected relative potency for the narcotic antagonists evaluated: DM-NALT greater than NALT greater than NAL. Thus, the TST-response test is a rapid and quantitative bioassay for the evaluation of compounds for narcotic antagonistic activity.
Animals↗
Redox delivery system for brain-specific, sustained release of dopamine.
Dopamine was transformed into a redox chemical system for delivery to the brain. The lipoidal form allowed penetration of the blood-brain barrier. Oxidative and hydrolytic processes then transformed the delivery form into a quaternary ammonium precursor of dopamine. The quaternary ammonium precursor was rapidly eliminated from the general circulation, whereas that formed in the brain was locked in, thereby providing a significant and sustained brain-specific dopaminergic activity.
Animals↗
Prodrugs of 6-thiopurines: enhanced delivery through the skin.
Soft-alkylated derivatives of 6-mercaptopurine, its riboside, and 2-amino-6-mercaptopurine riboside have been prepared and evaluated to improve the delivery of the thiopurines through the skin. The soft-alkylated derivatives were prepared by the alkylation of the thiopurines with acylheteroalkyl halides under neutral or basic conditions. The penetration of the derivatives through hairless mouse skin was measured using diffusion cells. All of the derivatives underwent extensive degradation during their diffusion through skin so that the parent thiopurine, even in the case of the ribosides, was the major product observed in the receptor phase. The pivaloyloxymethyl derivatives showed the greatest potential for enhancing the penetration of the thiopurines through the skin. Among the 6-mercaptopurine derivatives, VII and XI were the most effective; they delivered 5 and 13 times, respectively, more 6-mercaptopurine than 6-mercaptopurine itself.
Animals↗
Improved delivery through biological membranes. 11. A redox chemical drug-delivery system and its use for brain-specific delivery of phenylethylamine.
A dihydropyridine in equilibrium pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. According to this, a biologically active compound linked to a lipoidal dihydropyridine carrier easily penetrates the blood-brain barrier. Oxidation of the carrier part in vivo to the ionic pyridinium salt prevents its elimination from the brain, while elimination from the general circulation is accelerated. Subsequent cleavage of the quaternary carrier-drug species results in sustained delivery of the drug in the brain and facile elimination of the carrier part. The concept is illustrated with phenethylamine as the drug and trigonelline as the quaternary carrier. One injection to rats of 1-methyl-3-(N-phenethylcarbamoyl)-1,4-dihydropyridine resulted in continuous build up in the brain of the corresponding 1-methyl-3-(N-phenethylcarbamoyl)pyridinium salt, reaching a maximum at about 80 min. At this time, the general circulation was practically void of either compound, while the accumulated carrier-drug species provided a source for sustained drug delivery only in the brain.
Alkaloids↗
Structure-activity relationships in the antiinflammatory steroids: a pattern-recognition approach.
A pattern-recognition technique has been used to determine structure-activity relationships for antiinflammatory steroids. Experimental results using the human vasoconstrictor test of McKenzie and Stoughton and the rat granuloma cotton pellet method of Meier were correlated with the various substructural descriptors. Steroids were classified into two categories according to potency, and a pattern-recognition method was applied to determine their relative ranking. The resulting structure-activity relationships obtained and the relative contributions of the various structural variables for both bioassays are discussed. A synergistic effect was predicted to be in operation between certain pairs of substituents.
Animals↗