Adjuvant lipid

Mineral Salts Immunostimulatory adjuvants Lipid particles Particulate adjuvants Mucosal adjuvants Aluminium hydroxide, aluminium phosphate, calcium phosphate Saponins (e.g., QS21), MDP derivatives, bacterial DNA (CpG oligos), LPS, MPL and synthetic derivatives, lipopeptides, cytokines (e.g., GM-CSF, IL-2, IL-12) Liposomes, virosomes, iscoms, cochleates, emulsions (e.g., Freunds adjuvant, SAF, MF59 ) Poloxamer particles, virus-like particles, PLG microparticles Cholera toxin (CT), mutant toxin (e.g., LTK63, LTR72), heat labile enterotoxin (LT), microparticles, polymerized liposomes, chitosan... 

Mineral salts Immunostimulatory adjuvants Lipid particles Particulate adjuvants Mucosal adjuvants... 

Several TLR-4 adjuvants for vaccines have been developed to date. An example of these is monopho-sphoryl lipid A (MJPL) a modified version of lipid A found in LPS [4]. It has been used extensively in clinical trials as it is far less toxic than LPS. It is hoped to use MPL in vaccines against infectious diseases, allergies and cancer. Derivatives of MPL have now been... 

In postmenopausal women, recently reported evidence supporting the use of aromatase inhibitors in the adjuvant setting is intriguing and may usurp the role of tamoxifen. Three different approaches to therapy have been undertaken with these new agents (1) direct comparison with tamoxifen for adjuvant hormonal therapy, (2) sequential use after 5 years of adjuvant tamoxifen therapy, and (3) sequential use after 2 to 3 years of adjuvant tamoxifen. Based on results of several studies, it has been concluded that therapy for postmenopausal women with ER-positive breast cancer should include an aromatase inhibitor.27,47 It is still unclear if the aromatase inhibitor should be used instead of tamoxifen or sequentially after receiving tamoxifen for 2 to 5 years.27 Concerns surrounding loss of bone density, changes in blood lipids, and cardiac and vascular disease require further study.27... 

Olbrich, C., Kayser, O., Muller, R.H., and Grubhofer, N., Solid lipid nanoparticles (SLN) as vaccine adjuvant study in sheep with a mycoplasma bovis antigen and stability testing, International Symposium of Controlled Release and Bioactive Material, 2000, 27, 293-294. 

Olbrich, C. and Muller, R.H., Tabatt, K., Kaiser, O., Schulze, C., and Schade, R., Stable biocompatible adjuvants — a new type of adjuvant based on solid lipid nanoparticles a study on cytotoxicity, compatibility and efficacy in chicken, Alternatives to Laboratory Animals, 2002, 30, 443 158. 

Joensuu H, Holli K, Oksanen H, Valavaara R (2000) Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer. Breast Cancer Res Treat 63 225-234... 

A variety of lipid adjuvants and protein mediators have also been shown to influence the immune response to antigens encapsulated in liposomes. The most widely used examples of such adjuvants for practical immunization procedures are endotoxin (including lipid A and lipopolysaccharide) and numerous types of lipophilic derivatives of muramyl dipeptide. 

LIPOSPHERES AS CARRIERS OF ADJUVANTS 5.4.1 Adjuvant Activity of Lipid A... 

A successful human trial of alum-adsorbed liposomes containing monophospho-ryl lipid A recently demonstrated that a formulation consisting of a combination of oil/water and adsorbent adjuvants can have considerable safety and efficacy and may be useful in the development of a potential vaccine against Plasmodium falciparum [29],... 

The adjuvant effect of different doses of lipid A in lipospheres was also examined by immunizing rabbits with lipospheres containing R32NS1 and prepared at different final concentrations of lipid A. The ELISA titers of the individual rabbit groups immunized, as determined by dilution of serum obtained at 6 weeks after primary immunization, have shown a gradual increase in IgG antibody titer with increasing... 

The effect of alum as adjuvant was also tested in the liposphere-vaccine formulation. In the presence of lipid A, enhanced immune response is obtained even in the absence of alum. This observation is very important because there is increasing concern about the toxic side effects of alum in the long term. Research has suggested a link between aluminum and diseases of the brain, including Alzheimer s disease. 

The adjuvant effect of lipid A on the immunogenicity of polymeric lipospheres was also tested [14], Incorporation of lipid A in PCL lipospheres had no effect on the IgG ELISA titers. However, in the case of PLA lipospheres, lipid A significantly increased the immune response to R32NS1 malaria antigen, resulting in IgG levels similar to those obtained with PCL lipospheres. The adjuvant effect of lipid A incorporated in PLA lipospheres was observed even after 1600-fold dilution of the rabbit sera [14],... 

The results presented in this chapter demonstrate that enhanced immunogenic efficacy can be achieved by using liposphere-based formulations, indicating the potential usefulness of lipospheres in the formulation of human and veterinary vaccines. The liposphere approach employs the fat-lipid environment to achieve several goals to serve as a carrier to protect the antigen, to serve as a depot, and to provide a surface interphase necessary for adjuvant activity. The ability to provide different surface... 

Finally, besides conventional liposomes that are made from natural (e.g., egg yolk and soybean) or synthetic phospholipids, novel liposomes called archaeosomes that are prepared from the polar ether lipids extracted from various archaeobacteria proved also interesting for the design of vaccines as peptide antigen carriers (71) and as powerful self-adjuvanting vaccine delivery vesicles that promote both humoral and cell-mediated immunity (72). Related to this, one can mention that pseudopeptides, which are less prone to proteolysis when conjugated to liposomes, were also competent in triggering a humoral immune response (73). 

While purified LPS displays potent immunostimulatory properties, it also induces various toxic side effects (Table 10.24), the most prominent of which is pyrogenicity. These effects render application of LPS as an adjuvant unacceptable. Both its immunostimulatory and toxic properties are mainly associated with the lipid A portion of the molecule. Attempts have been made to chemically or otherwise alter the lipid A portion in order to ameliorate the observed toxicity. 

The influence of physicochemical properties of liposomes, such as charge density, membrane fluidity, and epitope density, on the immune response elicited by antigens has been extensively studied [37]. In addition to antigens, other immune stimulators that are amphoteric muramyl peptides or lipid-soluble compounds, such as monophosphoryl lipid A or muramyl tripeptidyl-phosphatidylethanolamine, can also be incorporated into liposomes to increase their adjuvant effect in eliciting immune responses [34]. 

Diazepam, lorazepam, and midazolam are used for preanesthetic medication and as adjuvants during surgical procedures performed under local anesthesia. As a result of their sedative, anxiolytic, and amnestic properties, and their ability to control acute agitation, these compounds are considered to be the drugs of choice for premedication. (The basic pharmacology of benzodiazepines is discussed in Chapter 22.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which cause pain and local irritation. Midazolam is water-soluble and is the benzodiazepine of choice for parenteral administration. It is important that the drug becomes lipid-soluble at physiologic pH and can readily cross the blood-brain barrier to produce its central effects. 

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