1. A simple new quantitative micro method was developed to study the interaction of the cationic dye Alcian Blue 8GX and acid glycosaminoglycans under different conditions. After washing with ethanol the precipitated Alcian Blue-glycosaminoglycan complex was dissociated in Manoxol IB solution and the amount of bound dye measured spectrophotometrically. 2. Reaction profiles of complex-formation were determined in the presence of different concentrations of MgCl(2) at pH5.8, and could be used to study the critical electrolyte concentrations of glycosaminoglycans. At least 50mm-MgCl(2) was required to produce maximum precipitation of, and maximum uptake of, Alcian Blue by standard glycosaminoglycans. Maximum uptake of Alcian Blue by glycosaminoglycans in the urine of a patient with Hurler's syndrome required the presence of 25-50mm-MgCl(2). 3. Under standard conditions of maximum interaction, calibration curves for the quantitative determination of a series of standard glycosaminoglycans in 20mul volumes were nearly linear over the range 1-10mug. 4. The technique was used to determine the molecular binding ratios of Alcian Blue to glycosaminoglycans under controlled conditions.
Acyclovir {9-[(2-hydroxyethoxy)methyllguanine} is an acyclic guanine nucleoside analogue that is widely used clinically as an antiherpetic agent. Its limited absorption in humans after oral administration prompted the search for prodrugs. A congener, referred to as 6-deoxyacyclovir {2-amino-9-[(2-hydroxyethoxy)methyl]-9H-purine}, was synthesized and found to be 18 times more water soluble than was acyclovir. Surprisingly, this congener was readily oxidized to acyclovir by xanthine oxidase (EC 1.2.3.2). It was also oxidized by aldehyde oxidase (EC 1.2.3.1) largely to 8-hydroxy-6-deoxyacyclovir {2-amino-8-hydroxy-9-[(2-hydroxyethoxy)methyl]-9H-purine} and then to 8-hydroxyacyclovir {2-amino-6,8-dihydroxy-9[(2-hydroxyethoxy)methylj-9H-purine}. 6-Deoxyacyclovir and the major products of its oxidation by aldehyde oxidase lacked appreciable activity against herpes simplex type I in vitro. On the basis of these results, it was apparent that the success of 6-deoxyacyclovir as a prodrug in vivo would depend upon how well its desired activation by xanthine oxidase competed with the nonactivating oxidations by aldehyde oxidase.In rats dosed orally with 6-deoxyacyclovir, absorption was extensive and the major urinary metabolite was acyclovir. In two human volunteers, urinary excretions of acyclovir were 5-6 times greater than those typically observed after administration of equivalent doses of acyclovir itself. The areas under the plasma concentration-time curves for acyclovir were also 5-6 times greater. Plasma levels of acyclovir peaked soon after ingestion of the prodrug, indicating rapid absorption and metabolic conversion. These results suggested that 6-deoxyacyclovir might have clinical usefulness as a prodrug of acyclovir suitable for oral administration.Acyclovir {9-[(2-hydroxyethoxy)methylJguanine; Zovirax} is a clinically useful antiherpetic agent (1, 2). Intravenous (3, 4), oral (5), or topical (6, 7) administration provides-effective therapy. Only 15-20% of the dose is typically absorbed in humans after oral administration (8). This degree of absorption is adequate for efficacy against herpes simplex infections (5). However, greater absorption might be important in therapy against less sensitive viruses such as varicella-zoster virus (9). The clinical experience to date clearly indicates that although acyclovir represents a major therapeutic advance in the treatment of herpetic infections, a means of enhancing gastrointestinal absorption would significantly extend its usefulness.Considerable effort has been expended in attempts to find a prodrug that is well absorbed after oral administration and then converted to acyclovir. Esterification of the hydroxyl group of the (2-hydroxyethoxy)methyl moiety of acyclovir has been an approach taken by two separate laboratories (10,11). Unfortunately, those esters that have been tested showed no significant improvement in absorption after oral dosing (unpublished results).The 6-deoxy-6-amino congener of acyclovir {2,6-diamino-9-[(2-hydroxyethoxy)methyl]-9H-purine} (...
1. The effect of MgCl(2) concentration on the interaction of Alcian Blue 8GX and glycosaminoglycans in the urine of patients with mucopolysaccharidosis was studied by using a new quantitative micro method for the measurement of Alcian Blue-glycosaminoglycan complexes. This provided a means of measuring the critical electrolyte concentrations of urinary glycosaminoglycans. 2. Theoretical considerations based on the preceding paper (Whiteman, 1973) and experimental evidence provided here show that Alcian Blue 8GX may be used for the direct quantitative determination of total urinary glycosaminoglycans. The method is simple, requires sample volumes of 50mul or less, and gives results comparable with those obtained by other more complicated methods.
The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.
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