摘要:

AbstractThe trend to deliver drugs to defined areas of the body involves sophisticated carriers systems. In addition to thein vitrodrug release profile one must be aware of thein vivobehaviour of the dosage form and the drug. Gamma scintigraphy is an elegant way to gain insights of the actualin vivodistribution pattern of dosage forms. This technique relies on the use of radioactive tracers included into the medicament and selected so as to enable an optimum detection by a gamma ray camera. The choice of a convenient label enables thein vivodetermination of the targeting of the formulation administered through a large number of routes. The present paper reviews applications of gamma scintigraphy for the evaluation of dosage forms administered by the parenteral, rectal, buccal, nasal, pulmonary, and ophthalmic routes.

ISSN:1061-186X    

DOI:10.3109/10611869409015908

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractStudies were conducted to investigate the usefulness of polysulfone capillary fiber (PCF) as a drug delivery device for intraocular applications. Carboxyfluorescein (CF) was used as a model drug to prepare PCF-dye devices for bothin vitroandin vivokinetic studies. For thein vitrostudy, PCF-CF devices were incubated in 0.1 M phosphate buffer, pH 7.4 at 37°C, and CF release was quantified at various times up to 5 weeks.In vitroresults indicated a bi-phasic, sustained-release profile of CF from the PCF device for over 30 days. PCF-CF devices released 5% and 10% of their initial CF contents by the first and second day following incubation, respectively. By 10 days after incubation, approximately 50% of the dye content was released from the PCF-CF devices. The rate of dye release decreased thereafter, such that 65% and 90% of CF was released by 17 and 28 days after incubation, respectively. In a subsequent study, thein vivokinetics of the PCF-CF device were determined in the rabbit eye. PCF-dye devices were prepared with the following CF formulations: 1) microsphere-incorporated CF; 2) lyophilized liposome-encapsulated CF; or 3) micronized CF powder. A PCF-dye device was implanted in the vitreous cavity, and fluorophotometry from the retina to the anterior chamber was performed at various times up to 45 days to quantify fluorescein level. At the conclusion of the study, eyes were enucleated and examined for histopathology. The time-course study showed fluorescein level for up to 45 days in the vitreous. The midvitreous concentration-time profile indicated a CF t1/2 of 10 and 30 days for the PCF-CF powder and PCF-CF liposome preparation, respectively. In contrast, the PCF device prepared with microsphere-incorporated CF showed fluorescein level with a t1/2 of less than one week in the vitreous. Histological examination of the eyes implanted with PCF or PCF-dye device showed no sign of ocular toxicity. Collectively, these results indicated that the PCF device is biocompatible and may be useful for the extended release of drugs in the posterior segment of the eye.

ISSN:1061-186X    

DOI:10.3109/10611869409015909

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractBisphosphonates effectively inhibit osteoclastic bone resorption in diseases characterized by excessive bone loss. Liposome-encapsulated clodronate (dichloromethylene bisphosphonate) also is known to inactivate phagocytic cellsin vivo, and inhibit the growth of macrophage-like RAW 264 cellsin vitro. The macrophage suppressive effect of liposomal clodronate is of interest in autoimmune diseases, like rheumatoid arthritis, in which phagocytic cells are involved in inflammatory processes. Earlierin vivostudies suggested that liposomal clodronate is a far more potent inactivator of macrophages than liposomal forms of two other bisphosphonate compounds, pamidronate (3-amino-l-hydroxypropylidene bisphosphonate), and etidronate (l-hydroxyethylidene-l, l-bisphosphonate). We examined the growth inhibitory properties of these three bisphosphonates with macrophage-like RAW 264 cells and with other types of cellsin vitro. All three bisphosphonates encapsulated in liposomes effectively inhibited the growth of RAW 264 and CV1-P cells, while free drugs were 20-1000 times less potent growth inhibitors. Also, high extracellular calcium concentrations enhanced the potency of bisphosphonates for RAW 264 cells, indicating that, in addition to liposomes, the uptake of bisphosphonates by macrophages is mediated also by calcium. In all formulations, pamidronate was the most potent compound for the cells, with the exception of CV1-P cells, for which liposomal clodronate was the most potent. The effects of liposomal drugs were selective for highly endocytotic cells. The results suggest that liposome-encapsulated bisphosphonates could provide a specific tool to affect the function of macrophages and all three of these bisphosphonates are potentially effective as macrophage suppressors in autoimmune diseases.

ISSN:1061-186X    

DOI:10.3109/10611869409015910

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractA chemical delivery system (CDS) for enhanced delivery of dopamine to brain tissue, based on a dihydropyridine⟺pyridinium salt redox system, was modified to include an activated carbamate ester. The dihydronicotinate moiety was chemically attached to the amino group of dopamine (DA) by acylation with chloroethyl chloroformate, followed by condensation with sodium nicotinate under mild conditions. The product was selectively N-alkylated at the pyridine ring and subjected to regioselective reduction to the corresponding 1,4-dihydropyridine derivative, DA-CDSac.In vitrostability of the new compound was studied in phosphate buffers at mild acidic, physiological, and mild alkaline pH values. Oxidation studies showed facile conversion of the dihydronicotinate, DA-CDSac, is readily converted to the corresponding quaternary salt, both chemically and enzymatically.In vivostudies in rats did not detect sustained increases in brain levels of the quaternary salt after i.v. dosing with DA-CDSac. However, the new CDS appeared to change spontaneous locomotor activity in rats after i.v. administration which may be due to altered central DA neuronal activity.

ISSN:1061-186X    

DOI:10.3109/10611869409015911

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractTherapeutic effect of superoxide dismutase (SOD) and three derivatives: a conjugate with polyethylene glycol (SOD-PEG2), a canonized derivative (cSOD), and a mannosylated derivative (Man-SOD), on acute renal failure induced by ischemia/reperfusion was studied in rats. SOD and derivatives were administered intravenously to the rat after nephrectomy of the right kidney and before and after 60 min occlusion of the left renal artery. At 48 hr after reperfusion, the renal function was evaluated by determining the urinary excretion rate of14C-inulin injected intravenously. No therapeutic effect on the impaired renal function was shown in the case of low dose SOD (2600 unit/kg) treatment. In contrast, administration of cSOD which was shown to be taken up by the isolated perfused kidney from its capillary side and SOD-PEG2which maintained high plasma concentration exhibited significant therapeutic effect, as did SOD at ten-fold higher dose (26,000 unit/kg). On the other hand, renal damage was promoted by Man-SOD. Thus, the present study demonstrated that chemical modification may improve the therapeutic effect of SOD on the ischemic acute renal failure and increased SOD concentration in the renal vascular space is an important factor for the improved effect.

ISSN:1061-186X    

DOI:10.3109/10611869409015912

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractThis study was carried out to evaluate our monoclonal antibody (MoAb) toα-fetoprotein (AFP), 80G, as a carrier for targeting AFP-producing hepatoma. Pharmacokinetic analysis showed that the MoAb 80G was actively incorporated into AFP-producing HuH-7N cells (xenograft of human hepatoma cell line, HuH-7) in nude mice. Four conjugates composed of MoAb 80G, and a type 1 ribosome-inactivating protein, gelonin, were prepared. They involve two disulfide-linked and two thioether-linked conjugates. The binding activity of conjugates against AFP remained as high as that of intact 80G according to enzyme-linked immunosorbent assay. The in vitro cytotoxic effects of all the conjugates were specific against AFP-producing HuH-7 cells. Of these conjugates, two containing gelonin modified with 2-iminothiolane were more potent than the others. They showed significant antitumor activity upon AFP-producing HuH-7N cells in nude mice. However, the disulfide conjugate was more toxic to mice than the thioether conjugate judging from the loss in body weight and the liver damage. These results suggest that our MoAb 80G is a suitable carrier for targeting AFP-producing hepatoma cells, and that the noncleavable thioether conjugate is promising as an AFP-producing hepatoma-targeted drug delivery system.

ISSN:1061-186X    

DOI:10.3109/10611869409015913

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractWe have used the rat air pouch model of inflammation and S(+)ibuprofen as an experimental model system to enable the quantitative assessment of the pharmacokinetic determinants of site specific drug delivery. S(+)ibuprofen (50&1mg/kg) was administered directly into six day old air pouches immediately following the injection of the irritant carrageenan. Serial exudate and plasma samples were collected and analysed for ibuprofen by HPLC. The procedure was repeated following administration of S(+)ibuprofen (20&5mg/kg) intravenously. The parameters describing events in the air pouch and plasma indicated linear kinetics over the doses employed. The dose normalised AUCs were then used to formulate a quantitative measure of benefit for S(+)ibuprofen delivered directly to the air pouch. A Drug Targeting Index (DTI) was calculated from the ratio of AUC in the air pouch and plasma following direct inrrapouch administration divided by the same ratio following intravenous administration and gave a value of 130. This pharmacokinetic measure of benefit represents the maximum advantage afforded by the site specific delivery of S(+)ibuprofen as the whole of the administered dose is delivered directly to the site of action.

ISSN:1061-186X    

DOI:10.3109/10611869409015914

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor

摘要:

AbstractPoly(amidoamines) are soluble polymers containing tertiary amino and amido groups regularly arranged along the macromolecular chain, and their net average charge alters considerably as pH changes from neutral to acidic leading to a change in conformation. This property provides the possibility to design polymer-drug conjugates that are, following intravenous administration, relatively compacted and thus protect a drug payload in the circulation, but following pinocytic internalisation into acidic intracellular compartments unfold permitting pH-triggered intracellular drug delivery. To study the feasibility of this approach, a covalent conjugate of a poly(amidoamine) (MBI) was prepared to contain the membrane lytic non-ionic detergent Triton X-100 (as a model), and its ability to lyse red blood cellsin vitrowas used as an indicator of conjugate conformation at different pHs. Although Triton X-100 was highly lytic at pH 5.5, 7.4 and 8.0, and the parent polymer MBI was not lytic under any conditions, the conjugate only showed concentration-dependent red blood cell lysis at pH 5.5. Moreover, incubation of human leukaemic cells (CCRF) with these substrates showed conjugate to be more toxic than MBI (IC50values of 100μg/ml and 650μg/ml respectively) and less toxic than Triton X-100 (IC50of 1μg/ml).

ISSN:1061-186X    

DOI:10.3109/10611869409015915

出版商:Taylor&Francis    

年代:1994

数据来源: Taylor