A new process allows microencapsulation of purified human hemoglobin and 2,3-diphosphoglycerate to form neohemocytes. The microcapsule membrane is composed of phospholipids and cholesterol. Neohemocytes are substantially smaller than erythrocytes, contain 15.1 grams per decaliter of hemoglobin, and have a P50 value (the partial pressure of oxygen at which the hemoglobin is half-saturated) of 24.0 torr. All rats given 50-percent exchange transfusions survived with only limited evidence of reversible toxicity. Normal serum glutamate-pyruvate-transaminase values at 1, 7, and 30 days after transfusion were consistent with minimal hepatotoxicity. The concentration of blood urea-nitrogen was elevated by 35 percent after 1 day but returned to normal by day 7. However, histopathology revealed normal kidneys on day 1 as well as on days 7 and 30. Neohemocytes cleared from the circulation of transfused rats with an apparent half-life of 5.8 hours.
We have analyzed the implications of a simple two-compartment mathematical model (Hargrove and Schmidt, 1989) to anticipate the limits of antisense oligodeoxyribonucleotide action within single cells. The steady-state equations are derived for four special cases representing the following mechanisms: (i) ribosome blockage, (ii) mRNA cleavage by RNase H, (iii) concurrent ribosome exclusion and RNase H action, and (iv) decreased delivery of mature mRNA to the cytoplasm due to transcriptional blockage, interference with nucleocytoplasmic transport, or splicing. Dose-response relationships have been derived for these mechanisms under ideal conditions. Our results indicate that frequently translated mRNAs producing stable proteins are the most attractive antisense targets because these protein levels are sensitive to the changes in the mRNA levels that can be effected using antisense oligodeoxyribonucleotides. The nonsteady-state solutions show that both mRNA and protein half-life can determine the kinetics of antisense oligonucleotide action. A rapid onset of effect will be observed when the mRNA is rapidly degraded and slowly translated and when the translated protein is rapidly degraded. When the protein is slowly degraded, the kinetics of effect are limited by protein half-life. When the translational rate constant is large compared to the absolute difference between the mRNA and protein degradation rate constants, the kinetics of antisense action are determined by both degradation rate constants but are limited by the slower of the two degradative processes. We also show that the steady-state and nonsteady-state solutions may be used to design experiments that discriminate among mechanisms of antisense action.
Rat red blood corpuscles were held stationary with respect to a continuously flowing solution in either a specially constructed centrifuge or in glass filters. The concentration of the solution was gradually decreased to cause the swelling and subsequent gradual osmotic hemolysis of the cells. The passage of the intracellular molecules --potassium, adenylate kinase, and hemoglobin-across the cell membranes and into the flowing solution was determined as a function of time. Ions and molecules begin passage across the membranes in the order of increasing molecular size. The initial flow of potassium is followed by the initial flows of hemoglobin and adenylate kinase. The flow of hemoglobin has been interpreted as the flows of hemoglobin monomers, dimers, and tetramers such that the time sequence is: potassium; hemoglobin monomer; adenylate kinase/hemoglobin dimer; and finally, hemoglobin tetramer. It is concluded that the stressed cell membrane has molecular sieving properties and that the exclusion limit (effective hole size) increases as a function of time during the initial stage,; of gradual osmotic hemolysis. The process of gradual osmotic hemolysis is discussed in terms of molecular sieving through stress-induced effective membrane holes. It is suggested that a portion of the membrane protein might form an elastic network which would account for the gradual increase in size and apparent homogeneity of the effective holes.A red blood cell can be considered an assemblyofintracellularmoleeules of various sizes separated from an extracellular fluid by a membrane. When the membrane is sufficiently stressed by either mechanical (Rand, 1964) or osmotic (Ponder, 1948) means, it becomes permeable to hemoglobin, and the cell hemolyzes. A detailed study of the process of osmotic hemolysis, that is, the yielding of the cell membrane to applied stress, would be expected to provide information concerning the structure of the cell membrane.Marsden and 0stling (1959) found that during drastic hemolysis low molecular weight dextran entered the cells to a greater extent than high molecular weight dextran. Hjelm, 0stling and Persson (1966) found a greater percentage of small molecular weight molecules released from the cells * This work was prepared under the auspices of the U.S. Atomic Energy Commission.
Tumor cells often metastasize through lymphatic channels. It follows that localization of antitumor agents in the lymphatics may be therapeutically beneficial. This study determines the extent to which lipid composition controls lymphatic transport of a model compound ((14)C-sucrose) in liposomes following intraperitoneal administration in rats. All liposomes tested had mean diameters of approximately 0.2 µm. Liposomes were administerd to thoracic duct cannulated rats, and (14)C was quantified in thoracic lymph, several lymph nodes, blood, urine, and peritoneal wash. Changing liposome composition altered the rate of absorption of (14)C from the peritoneal cavity, stability in biological fluids, and the relative ability of liposomes to be retained by lymph nodes. Stability in biological fluids (plasma and lymph) appeared to be a reasonable predictor of observed lymph node recovery. Direct measures of lymph node level alone were poor measures of the ability of liposomes to function as prototypal lymphatic drug carriers. Neutral liposomes were better at reaching the general circulation following absorption from the peritoneal cavity.
A physiologically based model is presented to aid prediction of the pharmacological benefits to be derived from the administration of a drug as a targeted drug-carrier combination. An improvement in the therapeutic index and an increase in the therapeutic availability are the primary benefits sought. A measure of the former is obtained from the value of the drug targeting index, a newly derived parameter. Both the drug targeting index and the therapeutic availability are directly calculable. The minimum information needed for approximating both parameters is the candidate drug's total-body clearance and some knowledge of the target site's anatomy and blood flow. Drugs with high total-body clearance values that are known to act at target tissues having effective blood flows that are small relative to the blood flow to the normal eliminating organs will benefit most from combination with an efficient, targeted carrier. Direct elimination of the drug at the target site or at the tissue where toxicity originates dramatically improves the drug targeting index value. The fraction of drug actually released from the carrier at both target and nontarget sites can radically affect index values. In some cases a 1% change in the fraction of the dose delivered to the target can result in a 50% change in the drug targeting index value. It is argued that most drugs already developed have a low potential to benefit from combination with a drug carrier. The approach allows one to distinguish clearly those drugs that can benefit from combination with targeted in vivo drug carriers from those drugs that cannot.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.