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The influence of different process variables on the number of large particles before and after autoclaving of a 40% V/V Bis-Perfluorobutylethene emulsion stabilized by egg yolk lecithin, made isotonic with blood, was examined. The... more
The influence of different process variables on the number of large particles before and after autoclaving of a 40% V/V Bis-Perfluorobutylethene emulsion stabilized by egg yolk lecithin, made isotonic with blood, was examined. The concentration of emulsifier, emulsification and autoclaving time and temperature, fill volume and the cooling gradient applied to the emulsion after autoclaving all affect the number of large droplets and hence the stability and acceptability of the finished product. This work suggests that validation of equipment and process to very exacting specifications and strict adherence to specified manufacturing protocol is essential for the reproducible production of fluorocarbon emulsions acceptable for intravenous administration.
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A novel method for characterization of size distributions of parenteral fluorocarbon emulsions is described. Prepared emulsions were centrifuged to sediment droplets above predetermined diameters out of a known supernatant sample volume... more
A novel method for characterization of size distributions of parenteral fluorocarbon emulsions is described. Prepared emulsions were centrifuged to sediment droplets above predetermined diameters out of a known supernatant sample volume using the Bostok-Stoke's equation. Centrifugation times may be calculated using centrifuge parameters and physical properties of the fluorocarbon oil phase and the dispersion medium. The fluorocarbon content of the supernatant sample volume at successive centrifugation times was determined both by densitometry and by Gas Chromatography. A close correlation was found between the two methods. The density data was processed and converted into a volume distribution histogram by means of a program written in BASIC. The speed, simplicity of use, non reliance on costly equipment and good correlation to absolute particle counting methods makes the density method suitable for submicron size characterization.
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This Stimuli article summarizes the thinking of the USP Excipient Monographs 2 Expert Committee and USP staff regarding a class of excipients—collectively labeled co-processed excipients—that have been and continue to be introduced into... more
This Stimuli article summarizes the thinking of the USP Excipient Monographs 2 Expert Committee and USP staff regarding a class of excipients—collectively labeled co-processed excipients—that have been and continue to be introduced into the National Formulary (NF). This article presents some suggested criteria for acceptance of such monograph proposals into NF and solicits public input.
Signaling pathways that upregulate melanization in the retinal pigment epithelium (RPE) may also be implicated in the downregulation of rod outer segment (ROS) phagocytosis by the RPE. Melanization activating pathways may also modulate... more
Signaling pathways that upregulate melanization in the retinal pigment epithelium (RPE) may also be implicated in the downregulation of rod outer segment (ROS) phagocytosis by the RPE. Melanization activating pathways may also modulate oxygen consumption by the photoreceptors, apolipoprotein E4 levels, and the rate of photoisomerization events such that the net effect may be a reduction in drusen and/or lipofuscin accumulation. An increase in melanin at the apical microvilli of the RPE may shield ROS from light thereby contributing in part to the decrease in the rate of ROS phagocytosis. This decrease in ROS phagocytosis by the RPE may serve to maintain a balance between ingestion and degradation/recycling thereby avoiding an increase to its already substantial metabolic load. Several experimental drugs for age related macular degeneration (ARMD) coincidentally are also capable of decreasing the rate of ROS phagocytosis. This review attempts to identify the signaling pathways that m...
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The development of a simple method for rapid screening of antioxidants in the preformulation phase of drug development is reported. Using an easily oxidizable drug substance containing a tetrahydroisoquinoline nucleus, the relative... more
The development of a simple method for rapid screening of antioxidants in the preformulation phase of drug development is reported. Using an easily oxidizable drug substance containing a tetrahydroisoquinoline nucleus, the relative antioxidant efficacies was determined by simultaneous measurement of dissolved oxygen depletion and drug disappearance rates in presence and absence of antioxidants by oxygen polarographic and high performance liquid chromatographic (HPLC) methods, respectively. Results showed an inverse correlation between oxygen depletion and drug disappearance rates (R2 > 0.85). In contrast, such a high correlation was not obtained when the standard redox potential of these antioxidants was used as a predictor of drug disappearance rates (R2 > 0.50). The rate at which sodium metabisulfite (BIS) and glutathione depleted dissolved oxygen was reduced in the presence of drug, indicating possible reaction between either of the two antioxidants and drug (OHM-11252). He...
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... STABILITY AND EFFICACY Shireesh P. Apte and Sydney O. Ugwu ... Colloids Surfaces B: Biointerfaces 1999;15:161176. 3. Peek LJ, Brandau DT, Jones LS, Joshi SB, and Middaugh R. A systematic approach to stabilizing EBA-175 RII-NG for use... more
... STABILITY AND EFFICACY Shireesh P. Apte and Sydney O. Ugwu ... Colloids Surfaces B: Biointerfaces 1999;15:161176. 3. Peek LJ, Brandau DT, Jones LS, Joshi SB, and Middaugh R. A systematic approach to stabilizing EBA-175 RII-NG for use as malaria vaccine. ...
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Given the propensity of a large number of melanogenic pathways that can be modulated by cellular redox status, a causal role of the deficiency of ocular pigments such as melanin in the pathogenesis of age-related macular degeneration and... more
Given the propensity of a large number of melanogenic pathways that can be modulated by cellular redox status, a causal role of the deficiency of ocular pigments such as melanin in the pathogenesis of age-related macular degeneration and evidence that melanin production does occur in the adult eye, it seems not improbable that antioxidants (or agents that modify cellular redox status) may have melanin stimulatory (or inhibitory) effects that are superimposible on their effects as mere free radical scavengers. More empirical studies are needed to investigate this phenomenon so that antioxidant therapy may prove more beneficial to patients with ocular degenerative diseases.
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The state of aggregation of the polymer melanin may determine its propensity to act either as an antioxidant or as a pro-oxidant. Age-related alterations in its state of aggregation are suggested to alter the degree of polymerization so... more
The state of aggregation of the polymer melanin may determine its propensity to act either as an antioxidant or as a pro-oxidant. Age-related alterations in its state of aggregation are suggested to alter the degree of polymerization so as to confer increased pro-oxidant propensity to the melanin polymer. Degradative processes in/of melanosomes and lysosomes in the retinal pigment epithelium (RPE) appear to be intimately connected so that they may involve exchange of contents between these two organelles. An increased pro-oxidant environment inside lysosomes has been associated with preventing the digestion of cellular components including photoreceptor outer rod segments partly by altering function of lysosomal hydrolases. It is speculated that age-related accumulation of low-molecular-weight phototoxic pro-oxidant melanin oligomers within lysosomes in the RPE may be partly responsible for decreasing the digestive rate of incorporated cellular components (including photoreceptor outer rod segments) which may lead to lipofuscin formation. More work is required to definitively refute or support such a hypothesis.
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Several hypotheses have explicitly implicated the role of an altered redox status of melanin in the aetiology of melanoma and macular degeneration. The balance between the intrinsic anti-oxidant and pro-oxidant properties of melanin is... more
Several hypotheses have explicitly implicated the role of an altered redox status of melanin in the aetiology of melanoma and macular degeneration. The balance between the intrinsic anti-oxidant and pro-oxidant properties of melanin is lost, resulting in an altered redox phenotype. We propose that such an alteration of the redox status of melanin may arise, in part, due to suboptimal conditions for the effective polymerization of melanin precursors. We suggest that a decrease in the degree of polymerization or molecular weight of the melanin polymer may cause an alteration of the redox status of the polymer towards a more pro-oxidant state. A higher propensity of smaller oligomers to complex metals, coupled with an upregulation of metallothionein expression, results in increased production of free radicals including the superoxide anion. This, in association with an increase in the rate of tyrosinase degradation, a decrease in the rate of tyrosinase activation, alterations to template protein structure or alterations in the kinetics of the oxidation of tyrosine via the Raper-Mason pathway, may result in an overcoming of the cellular anti-oxidant pool, an increased susceptibility to oxidative stress and alterations to the reaction kinetics of melanogenesis, thus setting up a cycle of increasing oxidative stress and proliferation leading to the leakage of melanin monomers outside the organelle, thereby causing cytotoxicity and necrosis.
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Tyrosine kinase inhibitors may serve as ligands for kinases that are involved in normal cell differentiation or repair, thereby leading to toxicity. It may be possible to target such inhibitors to tumor cells by coupling them to... more
Tyrosine kinase inhibitors may serve as ligands for kinases that are involved in normal cell differentiation or repair, thereby leading to toxicity. It may be possible to target such inhibitors to tumor cells by coupling them to hypoxia-activated bioreductive molecules. Such coupling can utilize or incorporate bonds that have a propensity to be preferentially oxidized by thiols such as intracellular glutathione (GSH). The resulting depletion of GSH may increase redox-mediated apoptosis. The resultant molecule is hence projected to act via multiple cell killing mechanisms: (i) inhibition of tumor kinases, (ii) tumor DNA disruption and (iii) causing increased redox-mediated apoptosis.
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This Stimuli article summarizes the thinking of the USP Excipient Monographs 2 Expert Committee and USP staff regarding a class of excipients—collectively labeled co-processed excipients—that have been and continue to be introduced into... more
This Stimuli article summarizes the thinking of the USP Excipient Monographs 2 Expert Committee and USP staff regarding a class of excipients—collectively labeled co-processed excipients—that have been and continue to be introduced into the National Formulary (NF). This article presents some suggested criteria for acceptance of such monograph proposals into NF and solicits public input.