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Biomedical subjects

R H Hammer

Publications and source records attributed to R H Hammer.

At least 19 recordsLinked to original sources
PubMed1993

Expression of human apolipoprotein B100 in transgenic mice. Editing of human apolipoprotein B100 mRNA.

Apolipoprotein B (apoB) is a large glycoprotein that circulates in plasma as a major constituent of numerous lipoproteins. ApoB exists in two forms: apoB48 and apoB100. ApoB48 is identical in sequence to the N-terminal region of apoB100 and is generated by sequence-specific mRNA editing of the apoB100 transcript. Here, we describe the development of a line of mice expressing a human apoB transgene driven by promoter/enhancer sequences from the transthyretin gene. In these mice, immunodetectable human apoB100 is synthesized by the liver, kidney, and brain. Human apoB100 is found in low concentration (approximately 0.1 mg/dl) in the plasma of the transgenic mice and circulates in the low density lipoprotein fraction. The hepatic human apoB100 transcripts undergo mRNA editing at only slightly lower efficiency than the endogenous mouse apoB100 message. Therefore, there is no absolute species specificity to the apoB100 mRNA editing process.

Animals↗
PubMed1993

Soft drugs--XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine.

Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.

Animals↗
PubMed1993

Soft drugs--XVI. Design, evaluation and transdermal penetration of novel soft anticholinergics based on methatropine.

Atropine has been reported to produce unwanted systemic side effects on topical administration into the eye. The same problem could arise when atropine is used topically as a suppressant of eccrine sweating. In this study, the principles of soft drug design were applied to methatropine. A hypothetical carboxylate metabolite of methatropine was reactivated by esterification with cyclic and alicyclic alcohols to yield a series of compounds (3a-g). In vitro evaluation by guinea pig ileum assay indicated that the compounds are potent anticholinergics and the lead carboxylate metabolite is about 60 times less potent than the most active compound of the series. The activity was found to decrease with the increasing side chain length. The n-octanol/water partition coefficients were found to be directly dependent on the chain length for the compounds made with straight chain alcohols. The transdermal permeability coefficients across the hairless mice skin were found to be directly dependent on the partition coefficients. The soft drugs are found to metabolize extensively during the penetration process compared to the unmetabolizable nature of methatropine. The soft drugs reported in this study will probably be able to elicit a local action at the site of application but will probably be metabolized rapidly in the systemic circulation, thereby avoiding the systemic side effects with a consequent increase in the therapeutic index.

Administration, Cutaneous↗
PubMed1993

Soft drugs 15: mydriatic activity and transcorneal penetration of phenylsuccinic soft analogs of methscopolamine as short acting mydriatics.

Soft drug analogs of methscopolamine (4 a-c) were tested for mydriatic activity in rabbits' eyes. After unilateral administration of equieffective doses, the AUC24hrs and the mydriatic recovery times were found to be significantly lower with the soft drugs compared to methscopolamine. At equieffective doses, the AUC24hrs for soft drugs ranged from 22.4% to 60% of that of methscopolamine. Significant dilation of the untreated eye was observed with methscopolamine but not with the soft drugs after unilateral administration. Soft drug 4a exhibited only 10.4% of the AUC6hrs (untreated eye) of that of methscopolamine. Shorter durations of mydriatic action combined with potentially reduced systemic side effects make these compounds candidates for further study. In vitro rabbit transcorneal penetration of soft analog 4a was found to be significantly higher than methscopolamine.

Animals↗
PubMed1993

Soft drugs. 13: Design and evaluation of phenylsuccinic analogs of scopolamine as soft anticholinergics.

Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine. Selected aliphatic and cycloaliphatic esters (4a-e) of a hypothetical metabolite (2a) of methscopolamine with a phenylsuccinic acid basic structural moiety were designed and found to have anticholinergic activity and to revert to the original hypothetical metabolite in biological media with fairly short half lives. The pA2 values of the soft drugs were determined and the hypothetical metabolite was found 100 times less potent than the most potent compound (4a) of the series. The anticholinergic activities were found to be dependent on the length of the side chain alcohol.

Animals↗
PubMed1993

Soft drugs. 12: Design, syntheses and evaluation of soft anticholinergics.

Concepts involved in the design of soft drugs (drugs which, after achieving their therapeutic role, are metabolized in a predictable manner and at a controlled rate to non-toxic moieties) have been applied to methscopolamine (1). Selected aliphatic and cycloaliphatic esters (3) of a hypothetical carboxylic acid metabolite (2) of methscopolamine were designed and found to have anticholinergic activity. Six soft drug analogs of methscopolamine were tested for mydriatic activity in rabbit eye. At equieffective doses, the AUC24 hrs and the mydriatic recovery time were found to be significantly less with some of the soft drugs compared to methscopolamine and soft drug 3a was found to be shorter acting than tropicamide. At equieffective doses the AUC24 hrs for soft drugs ranged from 23.2% to 187% of that of methscopolamine. Significant dilation of the untreated eye was observed with scopolamine but not with the soft drugs after unilateral administration. Soft drug 3a exhibited only 2.3% of the AUC6 hrs (untreated eye) of that of methscopolamine.

Animals↗
PubMed1991

Short acting soft mydriatics.

Three soft drug analogs of atropine have been tested for mydriatic activity in rabbits' eyes and their in vitro metabolic pathway has been investigated in rat, rabbit and human blood. The three soft drugs were found to produce an equieffective mydriatic activity to atropine and tropicamide. At equieffective concentrations, their durations were shorter with AUC's 12-21% that of 0.25% atropine and 44-80% that of 0.2% tropicamide. The untreated control eyes were observed to dilate after unilateral ocular administration of atropine, but not with unilateral soft drug treatment. In vitro stability studies showed that the soft ethyl analog was less stable in rat blood and rat liver homogenate than in rabbit or human blood. The metabolic product of the soft ethyl derivative in biological media was proven to be the corresponding inactive acidic metabolite predicted by the soft drug design. The ultrashort durations and the potentially nontoxic systemic properties of the soft mydriatics offer promise for use in ophthalmoscopy and in other ocular procedures where a short acting anticholinergic type of mydriatic would be indicated.

Animals↗
PubMed1988

Novel 'soft' anticholinergic agents.

The concepts involved in the design of 'soft' drugs (drugs which, after achieving their therapeutic role, are metabolised in a predictable manner and at a controlled rate to non-toxic moieties) have been further applied in the case of atropine. Selected aliphatic and cycloaliphatic esters of a hypothetical, inactive acidic metabolite of atropine were designed and found to have atropine-like activity, and to revert to the inactive metabolite in rat liver homogenates. Peak anticholinergic activity, measured by the degree of antagonism of carbachol-induced spasms of guinea pig ileum strips, was observed when the esters contained a quaternary group. The in vitro stability of the esters was determined in human plasma, in pH 12 buffer solution, and in rat liver homogenate; the fastest rate of hydrolysis occurred in rat liver homogenate, and least sterically hindered esters degraded more rapidly than hindered esters. Synthesis of the esters was achieved in two stages. Phenylmalonic acid and the appropriate alcohol gave phenylmalonic acid monoesters, which, after reaction with tropine, afforded the required diesters. The tertiary amine group on the tropine moiety of the diesters then allowed the preparation of quaternary derivatives.

Animals↗
PubMed1977

Toxicity of alpha-phenyl-gamma-butyrolactone, a metabolite of glutethimide in human urine.

A novel metabolite, alpha-phenyl-gamma-butyrolactone, isolated from the urine of a glutethimide overdose victim, was synthesized and tested for biological activity in mice. Interperitoneal injections of this lactone caused severe toxicity at moderate dose levels. These results point to another metabolite of glutethimide contributing toxicity to patients severely intoxicated by the parent drug. An improved synthesis as well as complete spectral data of this lactone are also presented.

4-Butyrolactone↗
PubMed1976

Synthesis and characterization of a catechol metabolite of glutethimide (Doriden) in human urine.

A metabolite of glutethimide, 2-ethyl-2-(3,4-dihydroxyphenyl)-glutarimide, previously identified in enzymatically hydrolyzed human urine of overdosed victims was prepared synthetically and its chemical and spectral data compared to the proposed material. Results of these comparisons confirm the presence of a catechol metabolite of glutethimide in the urine of patients severely intoxicated by the parent drug.

Catechols↗
PubMed1976

Synthesis and characterization of alpha-phenyl-gamma-butyrolactone, a metabolite of glutethimide, phenobarbital and primidone, in human urine.

A novel metabolite, alpha-phenyl-gamma-butyfolactone has been isolated in urine samples of patients severely intoxicated by either glutethimide, phenobarbital, or primidone. This lactone was prepared synthetically and its spectral data and chromatographic properties were compared to those data obtained from the urine samples of drug overdosed victims. The results of these comparisons confirm the presence of this lactone in human urine following the ingestion of large amounts of the parent drug.

Glutethimide↗
PubMed1975

Phenolic metabolite, 2-ethyl-2(4-hydroxphenyl)-glutarimide in human urine following chronic ingestion of glutethimide (Doriden).

Urine samples from comatose patients, identified as having taken large amounts of the drug, glutethimide, were analyzed using gas chromatography, mass spectrometry, thin layer chromatography, and nuclear magnetic resonance spectrometry in order to identify metabolites of the parent drug. The phenolic compound 2-ethyl-2-(4-hydroxphenyl)-glutarimide was fully characterized as a new metabolite in human urine. Also 2-ethyl-2-(3-methoxy-4hydroxyphenyl)-glutarimide was proposed as a new metabolite of the parent drug. Other polar metabolites of the parent drug were also detected and partially characterized.

Chromatography, Gas↗
PubMed1975

Definitive characterization of the para-hydroxyphenyl metabolite of glutethimide in human urine.

The compound, 2-ethyl-2-(4-hydroxyphenyl)-glutarimide was prepared synthetically. Spectral data is presented which identifies this compound to be a metabolite of glutethimide isolated from enzymatically hydrolyzed human urine, following an overdose of the parent drug. New data supporting the structure of a minor metabolite, 2-ethyl-2-(3-methoxy-4-hydroxy)-glutarimide, is considered. Finally, gas chromatographic techniques have been perfected and are presented which yield complete purification of new metabolites of glutethimide.

Chromatography, Gas↗