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Biomedical subjects

K Juni

Publications and source records attributed to K Juni.

At least 19 recordsLinked to original sources
PubMed1998

Direct transport of 2',3'-didehydro-3'-deoxythymidine (D4T) and its ester derivatives to the cerebrospinal fluid via the nasal mucous membrane in rats.

We investigated the absorption and transport of 2',3'-didehydro-3'-deoxythymidine (D4T) and its ester prodrugs from the nasal cavity in rats. The absorption of D4T and its acetate (C2-D4T) was rapid and almost complete, although the hemi-succinate (Suc-D4T) was absorbed rather slowly; the plasma concentrations of the prodrug, Suc-D4T, and regenerated D4T remained unchanged throughout the experimental period (180 min). Concentrations in the cerebrospinal fluid (CSF) following intravenous (i.v.) and intranasal (i.n.) administration were also measured. After i.n. administration, drug concentrations were higher in the fraction derived from the subarachnoid space located close to the nasal mucosa than those in the fractions located far from the nasal cavity. This difference was not found following the i.v. administration of the drugs. Following nasal administration, the intact Suc-D4T was found in the CSF at a concentration higher than that of D4T, although transport of the intact prodrug to the CSF was not observed following i.v. administration. These results suggest that direct transport of the drugs from the nasal cavity to the CSF significantly contributes to the higher concentrations in CSF of D4T and/or its ester prodrugs, and indicate the possible value of nasal administration for the treatment of patients with AIDS dementia.

Administration, Intranasal↗
PubMed1998

Effect of several hydrophilic polymers on the permeation of morphine and salicylic acid through excised hairless rat skin.

Several hydrophilic polymers changed the cumulative amount of morphine (MOR) permeated through excised hairless rat skin from 1% MOR hydrochloride solution containing ethanol and l-menthol at concentrations of 40% and 5%, respectively, as permeation enhancers. Anionic polymers (carboxyvinylpolymer and methylvinylether-maleic anhydride copolymer) in the test solutions decreased the skin permeation of MOR, whereas cationic polymers (polyethyleneimine and chitosan) increased it, compared with that without polymers. Little change, however, was observed by the addition of nonionic polymers (hydroxypropylcellulose and polyethyleneoxide). On the other hand, the cationic and anionic polymers in the test solutions decreased and increased, respectively, the skin permeation of salicylic acid (SA) from the same enhancing system containing sodium salicylate. These opposite results were probably caused by the change in escaping tendency of the drugs from the vehicles, which was due to the drug-polymer interaction. (The escaping tendency has a great effect on the drug partition from the polymer solution to the skin barrier). The effect of hydrophilic polymers on the partition was then evaluated by Donnan membrane theory. The partition of MOR was increased and decreased by the presence of polymers having identical and opposite charge to MOR. The low partition of the drugs to skin may also be caused by low diffusion of the drugs in the polymer solutions. The drug release from the hydrophilic polymer solutions was then measured, and the release rate was found to have decreased in the presence of polymers having opposite charge to MOR and SA. It is suggested that these drug-polymer interactions changed the drug partition to skin thus changing the skin permeation of the drug.

Analgesics, Opioid↗
PubMed1996

Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats.

PURPOSE: To evaluate the effects of absorption enhancers in dry powders and in liquids, pulmonary absorption of salmon calcitonin (sCT) in various formulations was measured. METHODS: The dry powder of sCT was prepared by a freeze-drying method with a jet mill. After intratracheal administration of sCT dry powder and liquid (solution) preparations to rats, plasma sCT levels and calcium levels were measured. RESULTS: After intratracheal administration without absorption enhancers, sCT in the dry powder and in the liquid were absorbed nearly to the same degree. Absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-beta-cyclodextrin, octyl-beta-D-glucoside) were much more effective in the dry powder than in the solution. The reason may be that the enhancers added to the dry powder dissolved at high concentrations in a trace volume of the fluid lining the alveolar epithelium. CONCLUSIONS: The present results suggest that the pulmonary absorption of peptides and proteins can be greatly improved by formulating them into dry powders with smaller amounts of enhancers than in liquid dosage forms.

Absorption↗
PubMed1996

Nasal absorption of 2',3'-didehydro-3'-deoxythymidine (D4T) and its esters in rats.

Nasal absorption of 2',3'-didehydro-3'-deoxythymidine (D4T) and its esters (5'-acetyl D4T: C2-D4T and 5'-hemisuccinyl D4T: Suc-D4T) was investigated in rats. Bioavailability of D4T following intranasal (i.n.) administration was 98.0%, and the elimination from plasma was as rapid as that following intravenous administration of D4T. There seemed to be complete and rapid absorption of D4T from the nasal cavity. The plasma concentration-time profile of D4T following i.n. administration of C2-D4T was almost the same as that after administration of D4T itself. This suggests that C2-D4T was rapidly absorbed from the nasal cavity, and that some amount of dosing C2-D4T was hydrolyzed to D4T before entering the systemic circulation. In contrast, Suc-D4T showed slower absorption in the i.n. administration, and the plasma D4T level was maintained for a long period.

Absorption↗
PubMed1996

Intestinal absorption and first-pass elimination of 2', 3'-dideoxynucleosides following oral administration in rats.

Intestinal absorption and first-pass elimination of 2',3'-dideoxynucleosides (ddNs), including 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI) and 2',3'-didehydro-3'-deoxythymidine (D4T), following oral administration was investigated in rats. Enzymatic degradation of ddNs in rat intestinal washing and in the intestinal homogenate showed them to be stable in the washing with half lives of more than 140 h, whereas degradation of DDI in the intestinal homogenate was more than ten times as rapid as those of AZT and D4T. Intestinal absorption was studied in three segments of the rat intestine (duodenum, jejunum and colon) using an in situ closed-loop method. The area under plasma ddN concentration curve (AUC) and the residual percent of dose 1 h after dosing indicated a greater absorption of AZT and D4T in the upper intestinal tract than in the colon, very poor absorption of DDI in all segments, and considerable absorption of AZT in the colon. The AUC and the mean residence time (MRT) of ddNs following four different routes (intravenous: i.v., intra portal vein: i.p.v., intra duodenal: i.d. and intra gastric: i.g.) were measured using the in viva multiple sites of input method in rats. AZT and D4T were rapidly absorbed from the gastrointestinal tract and their bioavailability was more than 90%. DDI was less absorbed (33.02%) following i.d. administration compared with AZT and D4T. This poor absorption of DDI was partly attributable to its metabolism in the intestine.

Administration, Oral↗
PubMed1995

Permeability of peptides and proteins in human cultured alveolar A549 cell monolayer.

PURPOSE: The transport of peptides or proteins across the alveolar cell monolayer was studied in vitro in order to elucidate their transport pathway. METHODS: The permeability of 14 peptides or proteins and 6 dextrans with MW 1,000-150,000 was measured in cultured human lung adenocarcinoma A549 cell monolayers at 37 degrees C or 4 degrees C. The stability of the tested peptides and proteins was also evaluated. RESULTS: The permeability coefficients of these macromolecules across the A549 cell monolayer at 37 degrees C ranged from 10(-5) to 10(-7) (cm/sec), and exhibited a good inverse correlation with molecular weight. All macromolecules were stable throughout the transport experiment, and degradation by proteases was minimal. Permeability at 4 degrees C did not differ from that at 37 degrees C. Clear selectivity for direction of transport was not observed. CONCLUSIONS: These results suggested that the tested peptides and proteins appeared to penetrate the A549 cell monolayer via a paracellular route by passive diffusion.

Adenocarcinoma↗
PubMed1995

Stability, specific binding activity, and plasma concentration in mice of an oligodeoxynucleotide modified at 5'-terminal with poly(ethylene glycol).

Oligodeoxynucleotide (ODN) composed of 15 nucleotides was modified at 5'-terminal phosphate with hexylamine linker and chemically activated poly(ethylene glycol). This derivative showed improved characteristics in terms of enzymatic stability, binding activity, and in vivo retention in mouse. The data are discussed in comparison with those of corresponding unmodified and phosphorothioate ODNs.

Animals↗
PubMed1994

Study on pulmonary delivery of salmon calcitonin in rats: effects of protease inhibitors and absorption enhancers.

Effects of protease inhibitors and absorption enhancers on the absorption of salmon calcitonin (sCT) were evaluated after intratracheal coadministration to rats using the plasma Ca level as an index. Remarkable absorption enhancement could be attained with unsaturated fatty acids such as oleic acid and polyoxyethylene oleyl ether (absorption enhancers) and with chymostatin, bacitracin, potato carboxypeptidase inhibitor and phosphoramidon (protease inhibitors). sCT degrading enzymes had four times higher activity per total protein in membrane fraction of lung homogenates than the activity in cytosol fraction. These enzymes are thought to be serine proteases and metalloenzymes from the in vitro action profile of protease inhibitors. A good correlation between the in vitro activity of protease inhibitors and the in vivo enhancing effect on sCT activity suggested that membrane enzymes are responsible for the inactivation of sCT. Metabolic degradation and low permeability of sCT may be possible barriers to the absorption of sCT.

Absorption↗
PubMed1994

Nasal absorption of zidovudine and its transport to cerebrospinal fluid in rats.

The nasal absorption of zidovudine (AZT) and its subsequent transport to cerebrospinal fluid (CSF) was examined in rats. Both rapid absorption and a high CSF concentration were observed after the nasal application. Plasma and CSF concentrations of AZT increased when probenecid was coadministered with AZT. Thus, this nasal coadministration of AZT and probenecid could be useful for the treatment of AIDS patients with neuropathies.

Administration, Intranasal↗
PubMed1993

Prodrugs of 2',3'-didehydro-3'-deoxythymidine.

Six ester prodrugs of 2',3'-didehydro-3'-deoxythymidine (D4T) were synthesized, and their physicochemical properties were evaluated. Marked differences were observed. All of the prodrugs were chemically stable within the pH range 2-7. Hydrolysis of these esters was observed in all cases for four rat enzyme systems (plasma, liver, duodenum, and kidney), with D4T being regenerated. D4T or the prodrug was administered orally to rats, and the plasma concentrations of D4T and a corresponding prodrug were measured. The half-life of D4T after intravenous administration was 35.9 min. The half-life calculated from the terminal phase and the maximum concentration in plasma following oral administration of D4T were 35.9 min and 48.4 microM, respectively. After oral prodrug administration (with water or olive oil as a solvent), though none of the prodrugs was detected in plasma except for 5'-hemisuccinyl D4T and 5'-hemiglutaryl D4T with olive oil as a solvent, retention time of plasma D4T concentration was extended and the elevated D4T concentration in plasma decreased.

Administration, Oral↗
PubMed1992

Control of drug release with a combination of prodrug and polymer matrix: antitumor activity and release profiles of 2',3'-diacyl-5-fluoro-2'-deoxyuridine from poly(3-hydroxybutyrate) microspheres.

Drug release was controlled by a combination of prodrug and polymer matrix. Prodrugs of 5-fluoro-2'-deoxyuridine with different physicochemical properties were synthesized by esterification with aliphatic acids (propionate, n-butyrate, and n-pentanoate). Microspheres containing these ester prodrugs were prepared with poly(3-hydroxybutyrate) of three molecular weights (65,000, 135,000, and 450,000). The release rates from the spheres depended on both the lipophilicity of the prodrug and the molecular weight of the polymer. Regardless of the polymer, the relative release rates were propionate greater than butyrate greater than pentanoate. The release of butyrate and pentanoate from the spheres consisting of low-molecular-weight polymer (M(r), 65,000) was faster than that from the spheres of higher molecular weight (M(r), 135,000 or 450,000). A single intraperitoneal injection of spheres of the highest molecular weight polymer containing butyrate or pentanoate resulted in higher antitumor effects against P388 leukemia in mice than did free prodrugs given over a period of five consecutive days. The polymer sphere itself showed low toxicity to and good biocompatibility with mice and rats.

Animals↗
PubMed1992

Prodrugs of 2',3'-dideoxyinosine (DDI): improved oral bioavailability via hydrophobic esters.

Five ester prodrugs of 2'3'-dideoxyinosine (DDI) were synthesized for the purpose of improving oral bioavailability. The prodrugs, acetate (C2-DDI), octanoate (C8-DDI), stearate (C18-DDI), benzoate (Bz-DDI), and hemisuccinate (Suc-DDI) were proved to quantitatively regenerate their parent drug by enzymatic hydrolysis. Though the chemical stability of the prodrugs under acidic conditions was not improved, their solubility in water was significantly decreased by esterification, except for Suc-DDI. Bioavailability was evaluated by oral administration to rats. Two hydrophobic prodrugs (C8-DDI and Bz-DDI) showed higher absolute bioavailability (23.5% and 31.0%, respectively) than did DDI (15.2%), though that of C2-DDI (11.5%) and Suc-DDI (4.5%) was poor.

Administration, Oral↗
PubMed1991

In vivo and in vitro degradation of poly(3-hydroxybutyrate) in rat.

The inflammatory activity and biodegradation of poly(3-hydroxybutyrate) were examined. Poly(3-hydroxybutyrate) sheet did not cause any inflammation in the chorioallantoic membrane of the developing egg. The i.v. injection of 14C-labelled poly(3-hydroxybutyrate) granules showed that 86, 2.5 and 2.4% of the total radioactivity administered were distributed in the liver, spleen and lung, respectively, and the radioactivity decreased slowly but steadily in most tissues examined during 2 month. Crude extracts of rat tissues showed that the activity degraded the poly(3-hydroxybutyrate) granules in vitro.

Animals↗
PubMed1991

Controlled release of 5-fluoro-2'-deoxyuridine by the combination of prodrug and polymer matrix.

Poly(L-lactic acid) (L-PLA) microspheres containing 5-fluoro-2'-deoxyuridine (FUdR) or its ester prodrugs with saturated aliphatic acids (FUdR-Cn, n = 2, 3, 4, 5, 6, 8, 10 and 12) were prepared. The physicochemical and biological properties and antitumor activity of the L-PLA microspheres were studied. The lipophilicity of FUdR-Cn was increased by prolonging its acyl-promoieties. FUdR-C5, FUdR-C6, FUdR-C8, FUdR-C10 and FUdR-C12 showed almost complete incorporation into the microspheres, while incorporation of hydrophilic FUdR and FUdR-C2 was poor. The sustained release of FUdR from the microspheres containing FUdR-C4, FUdR-C5 and FUdR-C6 was obtained in the presence of esterase, and higher antitumor activity against P388 leukemia was observed in vivo. On the other hand, the release rates of FUdR from the microspheres containing FUdR-C10 and FUdR-C12 were very small, and their antitumor activity was much smaller than that of the free prodrug suspension. Effects of the susceptibility to enzymatic hydrolysis and the physiocochemical properties of prodrugs on the release profiles of FUdR from spheres were discussed.

Animals↗
PubMed1990

Ester prodrugs of zidovudine.

Ten novel ester prodrugs of zidovudine (azidothymidine; AZT) were synthesized with aliphatic acids (acetic-stearic), and the enzymatic regeneration of AZT from the prodrugs was investigated both in vitro and in vivo. The enzymatic hydrolysis rates of the AZT esters in the presence of mouse enzyme systems (plasma, liver, and intestine, and kidney) were highly dependent on the lengths of the acyl chains of the prodrugs. The caprate or caprylate of AZT showed the highest reactivity to three of the four enzyme systems; either the decrease or the increase in the acyl chain length resulted in the decrease of the reactivity to the enzymes. Zidovudine (AZT) and three of the prodrugs (acetate, caprate, and stearate) were administered to mice intraperitoneally, and the plasma concentrations of AZT and a corresponding prodrug were measured. The AZT concentrations in plasma following the acetate administration rapidly decreased with a half-life of 14.5 min. This tendency is similar to that shown in direct AZT administration. On the other hand, the concentrations following the caprate or stearate administration decreased slowly and were maintained for as long as 4 h after dosing. The prodrug concentrations in plasma after the prodrug administration were under the detection limit (0.01 micrograms/mL), except for acetate. The absence of the caprate and stearate in plasma may be attributed to the high hydrophobicity or favorable tissue distribution of the ester derivatives.

Animals↗
PubMed1990

Controlled release of 3',5'-diester prodrugs of 5-fluoro-2'-deoxyuridine from poly-L-lactic acid microspheres.

Poly-L-lactic acid (MW 6000) microspheres (PLA-MS) containing 5-fluoro-2'-deoxyuridine (FUdR) or four ester prodrugs of FUdR were prepared and examined with regard to the in vitro release kinetics. The incorporation efficiency of the lipophilic prodrugs into the PLA-MS was higher than that of FUdR or the hydrophilic prodrugs. The release of the lipophilic FUdR prodrugs from PLA-MS was sustained as compared with that of FUdR from PLA-MS. The release kinetics of the FUdR prodrugs appears to fit the Higuchi, Baker, and Lonsdale model in the early stage of the release process. The slope of the Baker and Lonsdale plots of the release of divaleryl-FUdR from PLA-MS decreased as the initial drug loading was decreased. The order of the release rates of FUdR prodrugs from PLA-MS with the same prodrug content was similar to that of the water solubilities of the prodrugs. These results suggest that the ester prodrugs could be released from PLA-MS by diffusion through water-filled capillaries or a series of pores rather than by diffusion through the PLA matrix.

Chemical Phenomena↗