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The successful conjugation of active theophylline molecules to two new multifunctional high-molecular weight poly(ethylene glycol) derivatives (MultiPEG) and their pharmacokinetic evaluations are reported. The drug loading was increased up to six times in comparison with commercial PEG of the same molecular weight. A clear increase of the time of persistence within the body and a concomitant improvement of the overall pharmacokinetic properties of those prodrugs were also observed. These studies sustain the use of these new PEG-based polymeric supports as a valuable alternative for an effective drug delivery system.

One of the most used and useful polymers, poly(ethylene glycol) (PEG) was used as a carrier for warfarin. The drug-polymer conjugate was freely water soluble at room temperature. The hydrolytic stability of the PEG-warfarin was investigated at physiological pH and confirmed the stability of the conjugate. In vivo release studies demonstrated a good release of parent drug, without the initial high plasma level of warfarin.

In the present paper two theophylline esters with poly (ethylene glycol) (PEG) and methoxy poly (ethylene glycol) (mPEG) were prepared. Quantitative yields of the pure products were obtained. Unlike the free drug, the drug-polymer conjugates are freely water-soluble at room temperature. In vitro release experiments in aqueous buffer demonstrate that both conjugates are stable in buffer of pH 7.4 and 1.2. In vivo release studies after oral administration of theophylline conjugates demonstrate a good release of parent drug.

Two known antiherpetic agents, acyclovir and valaciclovir, were coupled with activated poly(ethylene glycol). In vitro drug release studies demonstrated the conjugates to be stable in buffer solutions at pH 7.4 and 5.5, while only PEG-valacyclovir2 was stable in a buffer solution at pH 1.2. The ability of the macromolecular conjugate to release the free drug was also evaluated in plasma, in which the most stable prodrug also proved to be PEG-valacyclovir2. The derivatives are degraded in the presence of proteolytic enzyme. The rate of hydrolysis was monitored by HPLC-analysis.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

The two pairs of enantiomers of isoxazolidin-3-ones 3 and 4 were synthesized by means of Lipase PS-catalyzed hydrolyses of suitable racemic butyrates. The same butyrates were also employed as key intermediates in the preparation of racemic 3 and 4. The antimuscarinic potency of the new compounds was assayed in two in vitro functional tests. The eutomers (-)-3 and (-)-4 share the same stereochemistry (5R) of the most potent enantiomer of "azamuscarone" 2, a structurally related muscarinic agonist. Such a spatial arrangement around the chiral center of 2-4, coupled with the low values of eudismic ratio, represents an anomaly among the chiral muscarinic ligands. This anomaly was accounted for by the absence of a chiral center at C-2, a position whose configuration is crucial in determining the high enantioselectivity of muscarinic agonists and antagonists.

The synthesis of 2-(4-amino-5-chloro-2-methoxybenzamido)acetic acid 2, a metabolite of metoclopramide 1, has been accomplished through the coupling of 4-amino-5-chloro-2-methoxybenzoic acid 4 with glycine benzyl ester followed by a catalytic hydrogenation. Such a metabolite could not be detected directly in the human urines but only after its transformation into the corresponding methyl ester 6. Compound 6 was prepared both by condensing acid 4 with glycine methyl ester and by reacting acid 2 with diazomethane. HPLC analyses of biological samples were therefore performed after treatment with diazomethane. In five healthy volunteers, the percentage of 6 spanned the range 0.6-1.2%.

Many assay procedures have been devised to measure lipolytic activity, but none is without problems. It is for this reason that new methods are still being proposed. In this work we have investigated the use of two esters of p-nitrophenol, the palmitic acid and lauric acid esters, as substrates for a highly sensitive high-performance liquid chromatographic method. Data on recovery, specific activity and reproducibility are reported only for the lauric ester, because the palmitic ester turned out to be a very poor substrate.

A simple method for measuring angiotensin-converting enzyme activity in human serum was developed. Samples were incubated with hippurylhistidylleucine and the liberated hippuric acid was determined directly by reversed phase ion-pair high-performance liquid chromatography with UV spectrometric detection.

A rapid and specific high-performance liquid chromatographic assay for the quantitative determination of angiotensin-converting enzyme activity is described. Hippuryl-L-histidyl-L-leucine (Hip-His-Leu) is used as substrate and the released hippuric acid is measured. The procedure is accurate and precise and no extraction is required.

A simple, specific, and sensitive high-performance liquid chromatographic method for the determination of papaveraldine and papaverinol in papaverine hydrochloride injection has been developed. The compounds were chromatographed on a reversed-phase C-18 column using a water-methanol-acetonitrile solvent system containing sodium lauryl sulphate ion-pair reagent.

A simple, specific and sensitive high-performance liquid chromatographic method for the determination of p-amino benzoic acid (PABA) as impurity in procaine and procainamide hydrochlorides has been developed. The compounds were chromatographed on reversed phase C-18 using water-methanol-acetonitrile solvent system containing sodium lauryl sulphate ion-pair reagent.

A reversed-phase high-performance liquid chromatographic method has been developed to determine paracetamol, caffeine and propyphenazone in a typical tablet formulation with high accuracy and precision. The mobile phase is a linear water-methanol gradient.