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Biomedical subjects

L S Olanoff

Publications and source records attributed to L S Olanoff.

26 records · Page 2Linked to original sources
PubMed1981

The role of the fibrous capsule in the function of implanted drug-polymer sustained release systems.

Numerous studies have been carried out on drug-polymer sustained release systems designed for implantation. The majority of these efforts have been directed toward determining the in-vitro rate of drug release from specific systems or drug polymer combinations and the in-vivo studies have attempted to utilize analysis of the blood serum and excretory products as a measure of the release rate and behavior. To gain a better understanding of the influence of the local tissue environment and implant site on release behavior, we have investigated the release behavior of a gentamicin-silicone rubber system implanted in canines. Particular attention has been directed toward investigating the role that the fibrous capsule which eventually surrounds the implant plays in determining the rate and pattern of drug release. The drug burst effect was decreased by the use of a drug-free silicone rubber membrane on the gentamicin-silicone rod implant. Analysis for gentamicin in the tissue adjacent to the implant for periods up to four weeks indicated that the release rate was retarded by the development of the fibrous capsule. The temporal and spatial variations in gentamicin levels in the tissue surrounding the rod implants were determined. In addition, the influence of implant coating and gentamicin loading level in the implant on local tissue concentrations with time were also investigated. These studies provide evidence that the fibrous capsule surrounding a drug-polymer sustained release implant may influence the release behavior of the drug in an advantageous or disadvantageous manner depending upon the desired function of the sustained release system.

Animals↗
PubMed1980

Controlled release of tetracycline--III: A physiological pharmacokinetic model of the pregnant rat.

A controlled tetracycline delivery device, consisting of a membrane enclosed trilaminate disc fabricated from a series of 2-hydroxyethylmethacrylate/methylmethacrylate copolymers, demonstrated the ability to deliver tetracycline at zero-order rates in vitro and in vivo in rats and was applied to study the pharmacokinetics of tetracycline in the pregnant rat. The trilaminate discs containing tetracycline were implanted in pregnant Sprague-Dawley rats on the eighth day of gestation. The animals were sacrificed on days 19, 20, and 21 of gestation in order to measure the distribution of the controlled release tetracycline in the maternal, fetal, and placental tissues. Constant plasma tetracycline levels were attained in both the maternal and fetal circulations after 4 to 5 days postimplantation of the trilaminate discs. Placental transfer of tetracycline appeared rapid and no partitioning of the drug was observed between the maternal and fetal soft tissue (liver, kidney, G.I. tract, muscle, placenta) as measured over the last 3 to 4 days of the animal's gestational period. Highest tetracycline concentrations were determined in the fetal bone samples. In addition, some accumulation of the drug occurred in the amniotic fluid. A flow-limited pharmacokinetic model was constructed to simulate the distribution of tetracycline, delivered at a constant rate from the trilaminate device, in the pregnant rats. Predictions of fetal growth and maternal and fetal tissue tetracycline concentrations were in good agreement with the experimental measurements. The ability of these copolymer systems to deliver tetracycline at zero-order rates over extended periods offers numerous potential therapeutic and investigational applications, especially where such drug delivery characteristics are beneficial to the elucidation of physiological rate mechanisms, as in the pregnant animal.

Animals↗
PubMed1980

Sustained release of niridazole from silicone rubber implants for the treatment of Schistosoma mansoni infections.

Niridazole was incorporated into silicone rubber implants to investigate the potential of a sustained release of the drug in the therapy of murine schistosomiasis mansoni. The infected animals (200 cercariae for 6 weeks) were randomly divided into three groups: one group received silicone rubber implants containing 50% by weight niridazole; a second group received blank silicone rubber implants with no drug; and the third group received no implants. Mortality 4 weeks later was in excess of 80% for animals with no implants or with the blank silicone rubber implants. In contrast, 10% mortality was observed in the mice receiving the niridazole-silicone rubber implants over a 10-week period. The worm burden in the niridazole-silicone rubber implant group was reduced at 10 weeks post implantation by 77%.

Animals↗
PubMed1977

Perfusion trials with a collagen-immobilized enzyme in an extracorporeal reactor: activity, stability, and biocompatibility.

This paper is concerned with the evaluation of the in vivo performance characteristics of reconstituted bovine collagen as an insoluble carrier matrix fro therapeutic enzymes. The enzyme that was chosen as a model for this evaluation was E. coli L-asparaginase, which has been widely investigated as a soluble chemotherapeutic agent for the treatment of acute lymphocytic leukemia in humans (Oettgen et al., Cancer Res., 27, 2619, 1967 ; Beard et al., Brit. Med. J., 1, 191, 1970; Ohmuma et al., Cancer Res., 30, 2297, 1970). The results presented here were obtained from perfusion trials with a collagen-asparaginase reactor incorporated into an extracorporeal circuit attached to the vascular systems of healthy mongrel dogs. A series of 1-2 hr perfusions were conducted with a single collagen-asparaginase membrane over a period of 4 months. Serum asparagine levels were reduced by more than 98% after 15-30 min perfusion time. Red blood cell (RBC), hemoglobin, hematocrit, and fibrinogen values remained constant during each perfusion. An average decrease of 48% in white blood cell (WBC) and 24% in platelet levels was observed, but these values began to rise slowly even before cessation of the perfusion. No serious toxic or antigenic reactions or mechanical or clotting difficulties were observed. In vitro activity, when assayed between perfusions, remained constant over a period of 4 months of intermittent use and storage. The potential advantages of collagen-enzyme complexes for the administration of therapeutic enzymes is discussed.

Animals↗
PubMed1975

Reduction of canine serum asparagine levels by L -asparaginase immobilized on collagen: a potential form of cancer chemotherapy.

These results suggest that asparaginase-collagen preparations, with activity and stability values surpassing those reported for other immobilization procedures, can be potentially utilized as an efficient extracorporeal chemptherapeutic device for the treatment of tumors, producing less side effects than the soluble enzyme therapy, for a given level of asparagine clearance.

Animals↗
PubMedDate not supplied

Protective effects of trans-13-APT, a thromboxane receptor antagonist, in endotoxemia.

The effect of the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist trans-7[2-(p-hydroxyphenethylamino)-cyclopentyl]-heptanoic acid (trans-13-APT) on certain pathogenic sequelae of endotoxic shock and associated changes in arachidonic acid metabolism in the rat was investigated. trans-13-APT, an analog of 13-azaprostanoic acid, was synthesized and found to block human platelet aggregation induced by the thromboxane mimetic U46619. Pretreatment with trans-13-APT did not significantly alter the elevations in plasma immunoreactive (i) TxB2 or iPGE, 0.5 or 4 h after the intravenous administration of Salmonella enteritidis endotoxin. However, in the trans-13-APT-pretreated group, 4 h after administration of the endotoxin, plasma i6-keto-PGF1 alpha was significantly (p less than 0.05) reduced to 1.2 +/- 0.3 ng/ml (n = 17) compared with vehicle-treated rats (2.4 +/- 0.5 ng/ml; n = 18). The elevation in plasma i6-keto-PGF1 alpha seen 0.5 h (n = 17/group) after endotoxin infusion was not altered by trans-13-APT. trans-13-APT also significantly (p less than 0.05) attenuated the endotoxin-induced fall in platelet count (135 +/- 27 X 10(3)/mm3 vs. 350 +/- 65 X 10(3)/mm3 and hypoglycemia (73 +/- 9 vs. 97 +/- 7 mg/dl), but not the leukopenia. Since the reticuloendothelial system may be an important source of iTxB2 and i6-keto-PGF1 alpha during endotoxemia, in vitro studies were conducted with adherent peritoneal cells. High concentrations of trans-13-APT (50 and 100 microM) significantly reduced (p less than 0.05) basal but not endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1 alpha by isolated adherent rat peritoneal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Quantitative account of propranolol metabolism in urine of normal man.

A recent study, identifying several sulfate conjugates, appears to have led to a full qualitative account of propranolol metabolism in man. The objective of the present investigation was to determine the quantitative fate of propranolol, including the relationship between the primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Single 80-mg oral doses of propranolol together with [3H]propranolol were administered to seven normal subjects. Urinary metabolites were determined by HPLC with radiometric detection after hydrolysis of glucuronic acid conjugates and fractionation by solvent extraction. About 90% of the dose was recovered in urine. Twelve metabolites accounted for 91% of the recovered dose. When examining the metabolites based on the primary metabolic pathways, 17% of the dose (range, 10-25%) was going through glucuronidation, 41% (range, 32-50%) through side-chain oxidation, and 42% (range, 27-59%) through ring oxidation. These data show that the net elimination of propranolol is largely due to oxidative metabolism. The relative contribution of the primary pathways is well reflected by the four major propranolol metabolites, i.e. propranolol glucuronide, naphthoxylactic acid, and the glucuronic acid and sulfate conjugates of 4'-hydroxypropranolol. These observations should greatly facilitate future studies of the biochemical mechanisms of propranolol disposition.

Adult↗