Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vivo evaluation of cyclic amino acid esters

Eighteen amino acid esters of the antiherpetic drug, acyclovir, were synthesized as potential prodrugs for oral administration. The esters were examined for in vitro antiviral activity against herpes simplex virus Type 1 (HSV-1). They were found to have less potency than the parent compound. Their efficiencies as prodrugs were evaluated in rats by measuring the urinary recovery of acyclovir. Ten prodrugs produced greater amounts of the parent drug in the urine. The L-amino acid esters were better prodrugs than the corresponding D- or D, L-isomers, suggesting the involvement of a stereoselective transporter. The L-valyl ester, 256U87, was the best prodrug. Sixty three per cent of its administered dose was excreted as acyclovir in the urine, a considerable improvement over acyclovir itself, for which this value was 19%. Since 256U87 was stable in aqueous solutions, its conversion to acyclovir in vivo was probably enzyme catalyzed. This L-valyl ester prodrug of acyclovir is now undergoing clinical evaluation.

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Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.7 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5102-5109

Author(s):

Venu Madhav K ◽

Somnath De ◽

Chandra Shekar Bonagiri ◽

Sridhar Babu Gummadi

Keyword(s):

Oral Bioavailability ◽

Oral Delivery ◽

Solid Dispersions ◽

In Vitro Release ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension. From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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FURTHER STUDIES ON THE ROLE OF PROTEASES IN THE ALLERGIC REACTION

Journal of Experimental Medicine ◽

10.1084/jem.113.2.359 ◽

1961 ◽

Vol 113 (2) ◽

pp. 359-380 ◽

Cited By ~ 32

Author(s):

Georges Ungar ◽

Takuso Yamura ◽

Jacqueline B. Isola ◽

Sidney Kobrin

Keyword(s):

Amino Acid ◽

Guinea Pig ◽

Proteolytic Activity ◽

Guinea Pigs ◽

Protease Activity ◽

Amino Acid Esters ◽

Protein Substrates ◽

Protease Activation ◽

Acid Esters

Protease activity was measured through the hydrolysis of synthetic amino acid esters in body fluids and tissues of guinea pigs, rats, mice, and humans. Significant in vitro activation was observed in serum and lung slices of sensitized guinea pigs on addition of the specific antigen. Increased proteolytic activity was also seen in reverse anaphylaxis. More marked activation occurred when guinea pig serum was treated with peptone and guinea pig or rat serum was treated with agar. Protease activation was demonstrated in specimens of human skin under the influence of a poison ivy extract or croton oil added in vitro. Urinary protease activity of guinea pigs increased significantly during the first hours of anaphylactic shock and very markedly in peptone shock. Peptone shock, elicited in mice pretreated with H. pertussis, was accompanied by a considerable increase in protease activity in the peritoneal fluid as compared with non-pretreated mice which were insensitive to peptone. Proteolytic activity resulting from the activation procedures was due to a number of proteases. The dominant substrate affinity and inhibition patterns suggest that serum and urine proteases are similar to but not identical with plasmin. Anaphylactic activation exhibited patterns different from those resulting from the action of anaphylactoid agents. Tissue enzymes are either of cathepsin- or chymotrypsin-type or mixtures of both. Some of the activated enzymes, although remarkably effective in hydrolyzing amino acid esters, show no activity on protein substrates. This does not justify, however, their designation as "esterases." They probably belong to the class of specific proteases acting only on a single or a small number of functionally significant protein substrates. There is at present sufficient evidence to prove not only that protease activation does occur in anaphylaxis and anaphylactoid conditions but also that it is an important component of the chain of reactions leading to the allergic response.

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