Enhanced Activity of Topical Hydrocortisone by Competitive Binding of Corticosteroid-Binding Globulin.

Atopic dermatitis of sensitive areas such as the face, particularly in children, is a difficult disease to treat as the standard therapeutic, topical steroids, is contraindicated for this application in children. Hydrocortisone (HC) can be used in these instances because it has been shown to be safe, but is often ineffective as it is a relatively weak steroid, especially at over-the-counter concentrations. To enhance the local topical activity of HC, the terminal inactive metabolite of prednisolone, Δ(1)-cortienic acid (Δ(1)-CA), is added to HC, as Δ(1)-CA preferentially binds transcortin, liberating more HC to elicit its therapeutic effect. Skin blanching studies, which are used to evaluate the potency of topical steroids, were employed to assess the ability of Δ(1)-CA to enhance the activity of HC. The results demonstrate that Δ(1)-CA, when applied in combination with HC, does indeed potentiate the vasoconstriction effect of topically applied HC, while having no effect alone. Thus, addition of the inert prednisolone metabolite Δ(1)-CA can increase the therapeutic effect of over-the-counter concentrations of HC when applied topically.

Pharmacokinetics of the sequential metabolites of loteprednol etabonate in rats.

Pharmacokinetics, metabolism and excretion of two sequential inactive metabolites of the soft corticosteroid loteprednol etabonate (LE), Delta1-cortienic acid etabonate (AE) and Delta1-cortienic acid (A), have been investigated in rats. Pharmacokinetic studies (two-compartment model, 10 mg kg(-1) intra-venous bolus of AE or A) found the elimination of both AE (t(1/2)(beta), 12.46 +/- 1.18 min; CL total, 101.94 +/- 5.80 mL min(-1) kg(-1); and K el, 0.24 +/- 0.02 min(-1)) and A (t(1/2)(beta), 14.62 +/- 0.46 min; CL total, 53.80 +/- 1.40 mL min(-1) kg(-1); and K el, 0.18 +/- 0.02 min(-1)) to be significantly faster than that previously determined for the parent LE (t(1/2)(beta), 43.41 +/- 7.58 min; CL total, 67.40 +/- 11.60 mL min(-1) kg(-1); and K el, 0.071 +/- 0.024 min(-1)). For metabolism and excretion evaluations, 1 and 10 mg kg(-1) of either AE or A were intravenously administered, and the urine and bile were collected. AE and A rapidly reached their peak concentrations in the bile and urine, and most of them were eliminated within one hour. Total cumulative excretions at 4 h after 1 and 10 mg kg(-1) injections were 85.51 +/- 3.38% and 67.50 +/- 2.67% for AE, and 71.90 +/- 3.72% and 37.73 +/- 2.69% for A in bile; and 4.84 +/- 1.87% and 13.85 +/- 3.27% for AE, and 24.28 +/- 8.44% and 22.35 +/- 1.12% for A in urine, respectively. After AE administration, the excretion of AE was > 90%, and A was < 10% in all cases, indicating that the elimination of AE was much faster than its metabolism (to A). In a manner similar to that seen for LE, dose-dependent elimination was observed both in AE and A. These results suggested that both AE and A were ideal leads for the design of soft steroids based on the inactive metabolite approach.

Pharmacokinetic and pharmacodynamic evaluations of the zwitterionic metabolite of a new series of N-substituted soft anticholinergics.

PURPOSE: This study was conducted to evaluate the zwitterionic common metabolite of a novel series of N-substituted soft analogs of glycopyrrolate both as racemates and as 2R isomers. METHODS: Activities were assessed using both in vitro (receptor binding assay, guinea pig ileum pA2 assay) and in vivo techniques (rabbit mydriatic response, rat cardiac effects). Pharmacokinetic characterizations in rats were also performed. RESULTS: The metabolite was highly water-soluble and very stable in buffer solutions as well as in rat biological media. Following i.v. administration in rats, it was very rapidly eliminated, mainly through renal excretion with a half-life of about 10 min. Receptor binding and guinea pig ileum assays indicated this metabolite as more than 1 order of magnitude less active than its parent soft drugs or glycopyrrolate. Moderate M3/M2 muscarinic receptor subtype selectivity was observed, further reducing the likelihood of cardiac side effects. The metabolite showed to some extent mydriatic effect and protective effect against carbachol-induced bradycardia, but of much shorter durations than glycopyrrolate; it had, however, no effect on resting heart rate. CONCLUSIONS: N-Substituted zwitterionic metabolites retain some, but only considerably reduced activity of their parent quaternary ammonium ester soft anticholinergic drugs, and they are very rapidly eliminated from the systemic circulation. They are suitable for their assigned role within the framework of inactive metabolite-based soft anticholinergic design.

Design, pharmacokinetic, and pharmacodynamic evaluation of a new class of soft anticholinergics.

PURPOSE: To design and evaluate a new class of soft anticholinergics with subtype selectivity. METHODS: A new class of soft anticholinergics was designed based on the "inactive metabolite" approach. Four compounds were synthesized. The potency and soft nature of the compounds were evaluated by receptor binding, cardiac, and mydriatic studies. Stability and pharmacokinetic studies were also performed on these newly synthesized soft anticholinergics. RESULTS: Receptor binding studies of the soft anticholinergics on cloned muscarinic receptors indicated pKi values in the range of 7.5 to 8.9. Two compounds, 9a and 13a, of the series showed muscarinic subtype receptor selectivity (M3/M2). In mydriatic studies, 13a and 13b showed shorter duration of action in the treated eyes than tropicamide. In the control eyes, significant dilation of pupils was found only in rabbits treated with atropine and tropicamide, indicating that the soft anticholinergics lack systemic effects because of their facile hydrolytic deactivation. Consistent with their soft nature, this new class of soft anticholinergics displayed much shorter cardiovascular effects in the carbachol-induced bradycardia (10 to 15 min) in rats than atropine (> 60 min). Stability and pharmacokinetic studies suggested that the new soft anticholinergics were rapidly eliminated from plasma (systemic circulation) after i.v. administration. CONCLUSIONS: A new class of anticholinergics was designed and synthesized, and the PK/PD evaluation confirmed they were potent "soft" anticholinergics; two of them showed muscarinic receptor subtype selectivity (M3/M2).

Synthesis and biological evaluations of brain-targeted chemical delivery systems of [Nva2]-TRH.

Various chemical delivery systems for [Nva2]-TRH were synthesized and their CNS activity was investigated and compared with that of a similar chemical delivery system of [Leu2]-TRH, previously studied. Sequential metabolism of the chemical delivery system delivered to the brain, starting with the conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, will provide the lock-in to the brain of the T+-chemical delivery system, which will undergo hydrolysis of the cholesteryl ester, formation of the Pr-amide and cleavage of the spacer-T+ part, allowing ultimately the sustained release of the active [Nva2]-TRH. The CNS activity was assessed by measuring the extent of antagonizing barbiturate-induced sleeping time in mice. The fully packaged DHT-Pro-Pro-Gln-Nva-Pro-Gly-OCh produced robust antagonism, reducing sleeping time from 89 min to 48 min, similar to the Leu2-analogue (49 min). However, the partially substituted [Nva2]-TRH analogues showed little or no CNS activity. The results indicate that the fully packaged delivery system is necessary to produce the successful brain targeting of the precursor construct and effective release of the Gln-Nva-ProNH2.

In vitro and in vivo evaluations of dihydroquinoline- and dihydroisoquinoline-based targetor moieties for brain-specific chemical delivery systems.

Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.