Arthritis Australia

By I. Jensgar. New Saint Andrews College. 2018.

Effect of positively and negatively charged lipo- somes on skin penetration of drugs purchase 100mg pletal visa. Lipid vesicles penetrate into intact skin owing to the transdermal osmotic gradients and hydration force cheap pletal 100mg. Skin hydration and possible shunt route pen- etration in controlled estradiol delivery from ultradeformable and standard liposomes. Lipid nanoparticles (solid lipid nanoparticles and nanostructured lipid carriers) for cosmetic, dermal and transdermal applications. Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles. Large disk-shaped structures (discomes) in non- ionic surfactant vesicle to micelle transitions. Diffusion of estradiol from non-ionic surfac- tant vesicles through human stratum corneum in vitro. Liposomes and niosomes as topical drug carriers: Dermal and transdermal drug delivery. Interactions of non-ionic surfactant vesicles with cultured keratinocytes and human skin in vitro. Microemulsions – Modern colloidal carrier for dermal and transdermal drug delivery. Submicron emulsion vehicle for enhanced transdermal delivery of steroidal and non-steroidal anti-inflammatory drugs. A study on the influence of emulsion droplet size on the skin penetration of tetracaine. Biodegradable polymer nanocapsules con- taining a sunscreen agent: Preparation and photoprotection. Polymeric nanoparticles composed of fatty acids and polyvinyl alcohol for topical application of sunscreens. Potential use of nanoparticles for transcutaneous vaccine delivery: Effect of particle size and charge. Dendrimer-mediated transdermal delivery: Enhanced bioavailability of indomethacin. Poly(amidoamine) dendrimers as skin penetration enhancers: Influence of charge, generation and concentration. Liposomes: A novel topical delivery system for phar- maceutical and cosmetic applications. Effect of size of TiO2 nanoparticles embed- ded into stratum corneum on ultraviolet-A and ultraviolet-B sun-blocking properties of the skin. Human skin penetration of sunscreen nanoparti- cles in vitro assessment of a novel micronized zinc oxide formulation. A new healthy sunscreen system for human: Solid lipid nanoparticle as carrier of 3,4,5-trimethoxybenzoylchitin and the improvement by adding vitamin E. Effect of nanoparticle encapsulation on the pho- tostability of the sunscreen agent, 2-ethylhexyl-p-methoxycinnamate. Poly-epsilon-caprolactone nanocapsules con- taining octyl methoxycinnamate: Preparation and characterization. Impaired skin barrier function in dermatologic disease and repair with moisturization. Transfersomes – A novel vesicular carrier for enhanced transdermal delivery: Development, characterization, and performance eval- uation. Oestradiol skin delivery from deformable liposomes: Refinement of surfactant concentration. A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis. Evidence for lymphatic transport of insulin by topically applied biphasic vesicles. Transdermal immunization with an integral membrane component, gap junctional protein by means of ultradeformable drug carriers, transfer- somes. Systemic and mucosal immune response induced by transcutaneous immunization using hepatitis B surface antigen-loaded modified liposomes. Efficient delivery of transgenes to human hair follicle progenitor cells using topical lipoplex. Structural and transfection properties of amine- substituted Gemini surfactant-based nanoparticles. Topical non-invasive gene delivery using Gemini nanoparticles in interferon- -deficient mice. Targeted gene delivery to skin cells in vivo: A comparative study of liposomes and polymers as delivery vehicles. Human skin sandwich for assessing shunt route pene- tration during passive and iontophoretic drug and liposome delivery.

At very low concentrations trusted pletal 50mg, drugs are more likely to exhibit first-order kinetics because hepatic enzymes are usually not yet saturated pletal 100 mg free shipping, whereas at higher concentrations, enzymes saturate, making zero-order kinetics more likely. Use dose pairs of 300 and 400 and concentration pairs of 10 and 18 to calculate Km. The steady-state plasma concentration resulting from a daily dose of 500 mg would be estimated from the line equation as follows: Rearranging gives: C, D. When using the t90% equation, examine what happens to t90% when dose greatly exceeds Vmax. Discuss several practical methods to determine when a nonlinear drug has reached steady state. Examine the "time to 90% equation" and note the value of Km that is used in this equation. Substitute several different phenytoin Km values based on a range of population values (i. Based on this observation, what value of Km would you use when trying to approximate the t90% for a newly begun dose of phenytoin? Discuss the patient variables that can affect the pharmacokinetic calculation of a nonlinear drug when using two plasma drug concentrations obtained from two different doses. Write a pharmacy protocol describing an appropriate phenytoin dosing and monitoring service. Explain how the various sources of pharmacokinetic variation affect pharmacokinetic parameters. Describe ways to avoid or minimize errors in the collection and assay of drug samples. These differences in drug effect are sometimes related to differences in pharmacokinetics. However, irrespective of pharmacokinetics, drug effects may vary among individuals because of differences in drug sensitivity. Age At extremes of age, major organ functions may be considerably reduced compared with those of healthy young adults. In neonates (particularly if premature) and the elderly, renal function and the capacity for renal drug excretion may be greatly reduced. Renal function declines at a rate of approximately 1 mL/minute/year after the age of 40 years. In the neonate, renal function rapidly progresses in infancy to equal or exceed that of adults. When dosing a drug for a child, the drug may need to be administered more frequently. Compared with adults, the neonate has a higher proportion of body mass made up of water and a lower proportion of body fat. The elderly are likely to have a lower proportion of body water and lean tissue (Figure 11-1) Both of these changes, organ function and body makeup, affect the disposition of drugs and how they are used. Reduced function of the organs of drug elimination generally requires that doses of drugs eliminated by the affected organ be given less frequently. With alterations in body water or fat content, the dose of drugs that distribute into those tissues must be altered. For drugs that distribute into body water, the neonatal dose may be larger per kilogram of body weight than in an adult. Disease States Drug disposition is altered in many disease states, but the most common examples involve the kidneys and liver, as they are the major organs of drug elimination. In patients with major organ dysfunction, drug clearance decreases and, subsequently, drug half-life lengthens. Some diseases, such as renal failure or cirrhosis, may even result in fluid retention and an increased volume of drug distribution. Alterations in drug clearance and volume of distribution require adjustments in the dose administered and/or the dosing interval. For most drugs, when clearance is decreased but the volume of distribution is relatively unchanged, the dose administered may be similar to that in a healthy person but the dosing interval may need to be increased. Alternatively, smaller doses could be administered over a shorter dosing interval. When the volume of distribution is altered, the dosing interval can often remain the same but the dose administered should change in proportion to the change in volume of distribution. Effect of Volume of Distribution and Impaired Renal/Hepatic Function on Drug Dose Clinical Correlate When adjusting a dose of a drug that follows first-order elimination, if you do not change the dosing interval, then the new dose can be calculated using various simple ratio and proportion techniques. For example, if gentamicin peak and trough serum drug concentrations, in a patient receiving 120 mg Q 12 hours), were 9 and 2. Likewise, one can check to see if this trough would be acceptable with this new dose: "if 120 mg gives a trough of 2. A 23-year-old male experienced a major traumatic injury from a motor vehicle accident. On the third day after injury, his renal function is determined to be good (creatinine clearance = 120 mL/minute), and his weight has increased from 63 kg on admission to 83 kg. Note that fluid accumulation (as evidenced by weight gain) is an expected result of traumatic injury.

This substructure may overlay the butyl amine group or may be located elsewhere in the molecule buy pletal 100mg visa. Molecules without the butyl amine substructure have a six atom aromatic system buy pletal 100 mg on-line, of which one is nitrogen, as most important structural feature. This aromatic chain is not closed to form a six-membered ring, meaning that this substructure is found not only in six- membered rings but also in aromatic systems containing fused five-membered rings etc. Since the ‘normal’ representation does not discriminate between aliphatic and aromatic bonds, it may lead to substructure contributions that are part of an aromatic ring system (Figure 2, e. We therefore tested whether the use of a special aromatic bond type was the more suitable representation. Substructure occurrences for the aromatic bonds representation are listed in Table 3. When comparing the substructures of this representation with those of the ‘normal’ representation, a large overlap of the common motif was observed. For both representations, the most important moiety is the nitrogen substituted with one or more alkane chains. From this data, a second hierarchy (Figure 4) was constructed that did not consider the ‘normal’ representation. This approach resulted in a different substructure set than with the ‘normal’ representation. This carbon tail is probably shorter due to the absence of contributing aromatic bonds that were represented as single bonds in the ‘normal’ representation. The first substructure with an aromatic bond was found at position 24 in the substructure list in Table 3, whereas in the ‘aromatic atoms and bonds’ representation the first aromatic substructure was found much higher in the substructure list, i. Iterating over the substructures with the ‘aromatic atoms and bonds’ representation leaves the impression that an aromatic ring is forming (Supporting Information: substructures 3 to 5 and 10 to 15 in Table 2). The reason for this is that aromatic rings that differ in size contribute the same open substructures to the appearance lists. Since closed five-membered rings and closed six-membered rings cannot be overlaid, the support for these substructures is much lower. Using this representation, a significant enrichment of the source sets can be accomplished, provided that bonds may be part of an aromatic system (Figure 1). Table 4 gives an overview of the most-significant substructures for each representation. The tree is the same for analysis with and without the results of the ‘normal’ representation, since this representation did not produce any most significant substructures. For this set, the aromatic bonds representation yielded the most significant finding (Table 4). Almost two-third of the compounds (depending on definition) in this set have a 85 Chapter 3 carboxamide or ester at the core of their scaffold, either linking two ring systems or linking a ring system with an aliphatic group. The high number of carboxamide and ester groups at the core of the molecules may reflect the simple organic reactions between alcohols and acids that have been used to construct the library. This possibly reflects efforts to make drugs that are more soluble (for increased bioavailability) or to create prodrugs. As opposed to Figure 3, we now see a butyl chain without the amine group at the top of the hierarchy. Substructures containing the amine group are found one level down in the hierarchy. Here, it is particularly remarkable that the substructures all contain a double bonded heteroatom. Note that the substructures do not have a geometric arrangement; the layout of double bonds and aromatic bonds is arbitrary. For this second analysis, we derived smaller, sampled sets next to the two original full sets. The sampled sets, which were more convenient to work with, had the same substructure profiles as the full sets. The hierarchical grouping and levels where substructure analysis was performed are schematically presented in Figure 6. A group within a group is called a subgroup; the group that contains the subgroup is denoted as the supergroup. Substructures that have a significant preference for either the subgroup or the supergroup are denoted as either specific or avoiding, respectively. Specific substructures are those that set ligands from one subgroup apart from ligands of the neighboring subgroups. Avoiding substructures are those that seem to avoid ligands of the subgroup but do occur in neighboring subgroups.

The rate of glutathione conjugate formation during exposure to the oxidation product in cultured cells was rapid cheap pletal 100mg otc, whereas formation after exposure to amsacrine was slow discount 50mg pletal with amex, suggesting a low rate of oxidation of amsacrine to its oxidation products, with subsequent conju- gation formation in this system (Robbie et al. In all of the phase I studies, the dose-limiting toxic effect was myelosuppression, resulting mainly in leuko- penia. Other effects included nausea, vomiting, fever, injection-site reaction, skin rash and discolouration (due to the yellow colour of the drug), mucositis and alopecia. Paraesthesia and hepatoxicity were seen in a few patients, but cardiac toxicity was not observed in one study (Louie & Issell, 1985). At these doses, the leukopenia is mild to moderate in most patients but more severe in around 30% of patients (Hornedo & Van Echo, 1985). Myelo- suppression is usually more severe in previously treated patients, and is much more severe with high doses of amsacrine (600–1000 mg/m2). Stomatitis and mucositis become more frequent with higher doses (> 120 mg/m2) (Slevin et al. Hepatoxicity has been reported, typically manifest as transient increases in serum bilirubin concentration and/or hepatic enzyme activity, but lethal hepatotoxicity has also been reported (Appelbaum & Shulman, 1982). Phlebitis occurred in up to 17% of patients in early studies with amsacrine (Legha et al. The more common effects were alterations in the electro- cardiogram and arrhythmia, but cardiomyopathy and congestive heart failure also occurred (Weiss et al. Amsacrine has been used safely in patients with pre- existing arrhythmia when a serum potassium concentration of > 4 mmol/L was main- tained (Arlin et al. Toxic effects on the gastrointestinal and central nervous system were observed at lethal doses in dogs (6. In subsequent studies, evidence of cardiotoxicity was not seen in rats (Kim et al. Intravenous dosing of rats at 1 or 3 mg/kg bw per day for five days resulted in hair loss, diarrhoea and leukopenia; these effects were reversible (Pegg et al. Local tissue reactions were seen when the drug was administered subcutaneously or intramuscularly to guinea-pigs or rabbits, but similar effects were seen after admin- istration of the vehicle alone, suggesting that the acidity of the vehicle (see above) may have been responsible (Henry et al. Skin rashes in personnel involved in bulk formulation of amsacrine prompted further studies in experimental animals. In the Magnussen and Kligman maximization test, amsacrine was extremely sensitizing to the skin of guinea-pigs when given as a challenge dose by direct application, while the vehicle alone produced almost no response. The animals were not sensitized for systemic anaphylaxis, however, and there was no detectable induction of antibodies in rabbits (Watson et al. There was no effect on post-spermatogonial stages and little effect on stem cells, and the sperm counts had recovered by day 56 (da Cunha et al. Eye, jaw and other skeletal malformations were observed in the fetuses at all doses. An increased frequency of resorptions and decreased fetal weight were observed at the intermediate and high doses (Ng et al. Day-10 rat embryos [strain not specified] cultured for 24 h in vitro were exposed for the first 3 h to amsacrine at concentrations of 10 nmol/L to 1 μmol/L. A dose-related increase in the frequency of malformations was observed at doses of 50–500 nmol/L, and 100% of the embryos were malformed at 500 nmol/L. The malformations consisted mainly of hypoplasia of the prosencephalon, microphthalmia and oedema of the rhombencephalon. Similar malformations were observed in the same system with etoposide (see the monograph on etoposide). Comparison of the concen- trations necessary to produce lethality and malformations in 50% of fetuses showed that amsacrine was 10 times and 20 times more potent, respectively, than etoposide (Mirkes & Zwelling, 1990). In a study reported only as an abstract, male mice were treated with a maximum tolerated dose of 15 mg/kg bw [no further details given] amsacrine and showed no signs of dominant lethal mutation. The positive effects required a dose of about 800 μg/plate, which is higher than those tested in mammalian cells. In Saccharomyces cerevisiae strain D5, amsacrine failed to induce the mitochondrial ‘petite’ mutation, but it was an effective mitotic recombinogen when testing was done under conditions permitting cell growth. The Chinese hamster cell line xrs-1 was hypersensitive to amsacrine treatment (Caldecott et al. Amsacrine caused chromosomal aberrations in cultured Chinese hamster cells, in various rodent cell lines, in HeLa cells and in cultured human peripheral blood lymphocytes. Fluorescence in-situ hybridization techniques revealed a high frequency of dicentrics and stable trans- locations in amsacrine-treated human peripheral blood lymphocytes. Additionally, amsacrine induced micronuclei and chromosomal aberrations in the bone marrow of non-tumour-bearing male and female mice. In male ddY mice, amsacrine increased the incidence of micro- nuclei in both hepatocytes and peripheral blood reticulocytes.