Lipoamino acid-based adjuvant carrier system: Enhanced immunogenicity of group a streptococcal peptide epitopes

Lipoamino acid-based synthetic peptides (lipid core peptides, LCP) derived from the type-specific and conserved region determinants of group A streptococci (GAS) were evaluated as potential candidate sequences in a vaccine to prevent GAS-associated diseases, including rheumatic heart, disease and poststreptococcal acute glomerulonephritis. The LCP peptides had significantly enhanced immunogenicity as compared with the monomeric peptide epitopes. Furthermore, the peptides incorporated into the LCP system generated epitope-specific antibodies without the use of any conventional adjuvant.

A Pilot Randomized Trial Comparing CD-34Selected Versus Unmanipulated Hemopoietic Stem Cell Transplantation for Severe, Refractory Rheumatoid Arthritis

Objective. Evidence from animal studies, case reports, and phase I studies suggests that hemopoietic stem cell transplantation (HSCT) can be effective in the treatment of rheumatoid arthritis (RA). It is unclear, however, if depletion of T cells in the stem cell product infused after high-dose chemotherapy is beneficial in prolonging responses by reducing the number of infused autoreactive T cells. This pilot multicenter, randomized trial was undertaken to obtain feasibility data on whether CD34 selection (as a form of T cell depletion) of an autologous stem cell graft is of benefit in the HSCT procedure in patients with severe, refractory RA. Methods. Thirty-three patients with severe RA who had been treated unsuccessfully with methotrexate and at least 1 other disease-modifying agent were enrolled in the trial. The patients received high-dose immunosuppressive treatment with 200 mg/kg cyclophosphamide followed by an infusion of autologous stem cells that were CD34 selected or unmanipulated. Safety, efficacy (based on American College of Rheumatology [ACR] response criteria), and time to recurrence of disease were assessed on a monthly basis for up to 12 months. Results. All patients were living at the end of the study, with no major unexpected toxicities. Overall, on an intent-to-treat basis, ACR 20% response (ACR20) was achieved in 70% of the patients. An ACR70 response was attained in 27.7% of the 18 patients who had received CD34-selected cells and 53.3% of the 15 who had received unmanipulated cells (P = 0.20). The median time to disease recurrence was 147 days in the CD34-selected cell group and 201 days in the unmanipulated cell group (P = 0.28). There was no relationship between CD4 lymphopenia and response, but 72% of rheumatoid factor (RF)-positive patients had an increase in RF titer prior to recurrence of disease. Conclusion. HSCT can be performed safely in patients with RA, and initial results indicate significant responses in patients with severe, treatment-resistant disease. Similar outcomes were observed in patients undergoing HSCT with unmanipulated cells and those receiving CD34-selected cells. Larger studies are needed to confirm these findings.

Description of stable pain in rheumatoid arthritis: A 6 year study

Objective. To study pain quality and variability in patients with rheumatoid arthritis (RA). Methods. Pain, disease activity, and functional status Were assessed 3 times over 6 years in an initial cohort of 120 clinic patients with chronic pain from RA. A pain visual analog scale and the McGill Pain Questionnaire (MPQ) were used to record pain intensity and quality. RA disease activity and function were measured. Results. There was no statistically significant difference in any measure over the 3 assessments. RA pain intensity was moderate. The MPQ showed that sensory components of the pain were described in terms of pressure and constriction. Pain related affect was described with adjectives suggesting positive psychological adaptation to pain. Conclusion. The. results indicate a general profile of no change in pain sensation, affect, and emotional quality in clinic monitored patients with ongoing RA and ongoing, moderate levels of disease activity and function. The MPQ provides qualitative detail to patient's report of pain severity that could be a useful addition to longterm documentation of RA outcome. Regular MPQ documentation of current pain in outpatients could indicate whether any significant change in pain levels is reflected in altered word selection that reflects physiological or psychological change, and could assist clinicians to select the most appropriate form of therapy for RA pain.

Inter-relationships between rheumatoid arthritis and periodontal disease

This review considers the considerable similarities between periodontal disease and rheumatoid arthritis (RA). While the etiology of these two diseases may differ, the underlying pathogenic mechanisms are remarkably similar and it is possible that individuals manifesting both periodontitis and RA may suffer from a unifying underlying systemic dysregulation of the inflammatory response. In light of these findings, the implications for the use of disease-modifying medications in the management of these two chronic inflammatory conditions is apparent. Further longitudinal studies and medication-based intervention studies are required to determine just how closely these two conditions are allied.

Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis

Hydroxychloroquine (HCQ) is an antimalarial drug that is also used as a second-line treatment of rheumatoid arthritis (RA). Clinically, the use of HCQ is characterized by a long delay in the onset of action, and withdrawal of treatment is often a result of inefficacy rather than from toxicity. The slow onset of action can be attributed to the pharmacokinetics (PK) of HCQ, and wide interpatient variability is evident. Tentative relationships between concentration and effect have been made, but to date, no population PK model has been developed for HCQ. This study aimed to develop a population PK model including an estimation of the oral bioavailability of HCQ. In addition, the effects of the coadministration of methotrexate on the PK of HCQ were examined. Hydroxychloroquine blood concentration data were combined from previous pharmacokinetic studies in patients with rheumatoid arthritis. A total of 123 patients were studied, giving the data cohort from four previously published studies. Two groups of patients were included: 74 received hydroxychloroquine (HCQ) alone, and 49 received HCQ and methotrexate (MTX). All data analyses were carried out using the NONMEM program. A one-compartment PK model was supported, rather than a three-compartment model as previously published, probably because of the clustering of concentrations taken at the end of a dosing interval. The population estimate of bioavailability of 0.75 (0.07), n = 9, was consistent with literature values. The parameter values from the final model were: (Cl) over bar = 9.9 +/- 0.4 L/h, (V) over bar 605 +/- 91 L, (k(d)) over bar = 0.77 +/- 0.22 hours(-1), (t(tag)) over bar = 0.44 +/- 0.02 hours. Clearance was not affected by the presence of MTX, and, hence, steady-state drug concentrations and maintenance dosage requirements were similar. A population PK model was successfully developed for HCQ.

Lipid and carbohydrate based adjuvant/carriers in immunology

This review discusses various issues regarding vaccines:what are they and how they work, safety aspects, the role of adjuvants and carriers in vaccination, synthetic peptides as immunogens, and new technologies for vaccine development and delivery including the identification of novel adjuvants for mucosal vaccine delivery. There has been a recent increase of interest, in the use of lipids and carbohydrates as adjuvants, and so a particular emphasis is placed on adjuvants derived from lipids or carbohydrates, or from both. Copyright (C) 2003 European Peptide Society and John Wiley Sons, Ltd.

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo-adjuvant MAD was not perceived by patients to be a major inconvenience. If neo-adjuvant MAD in the way tested can be demonstrated to lead to improved biochemical control and/or survival, then patients would view these therapeutic gains as worthwhile. Compliance with short-term goserelin was excellent, confirming that LH-RH analogues have a potential role in more long-term adjuvant treatment. However, for more protracted androgen deprivation, survival advantages and deleterious effects need to be assessed in parallel, in order to determine the optimal duration of treatment. (C) 2003 Elsevier Ireland Ltd. All fights reserved.

Phase 1 study of HPV16-specific immunotherapy with E6E7 fusion protein and ISCOMATRIX (TM) adjuvant in women with cervical intraepithelial neoplasia

Purpose: Persistent infection of cervical epithelium with high risk human papillomavirus (HPV) results in cervical intraepithelial neoplasia (CIN) from which squamous cancer of the cervix can arise. A study was undertaken to evaluate the safety and immunogenicity of an HPV 16 immunotherapeutic consisting of a mixture of HPV16 E6E7 fusion protein and ISCOMATRIX(TM) adjuvant (HPV16 Immunotherapeutic) for patients with CIN. Experimental design: Patients with CIN (n = 3 1) were recruited to a randomised blinded placebo controlled dose ranging study of immunotherapy. Results: Immunotherapy was well tolerated. Immunised subjects developed HPV16 E6E7 specific immunity. Antibody, delayed type hypersensitivity, in vitro cytokine release, and CD8 T cell responses to E6 and E7 proteins were each significantly greater in the immunised subjects than in placebo recipients. Loss of HPV16 DNA from the cervix was observed in some vaccine and placebo recipients. Conclusions : The HPV16 Immunotherapeutic comprising HPV16E6E7 fusion protein and ISCOMATRIX(TM) adjuvant is safe and induces vaccine antigen specific cell mediated immunity. (C) 2004 Elsevier Ltd. All rights reserved.

ISCOMATRIX (TM) adjuvant: An adjuvant suitable for use in anticancer vaccines

Human Papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are associated with cervical cancer development and progression and can therefore be used as target antigens for cancer immunotherapy. In this study we evaluated the immunogenicity in mice, of different vaccine formulations using recombinant HPV16 derived E6E7 or E7GST fusion proteins. When co-administered with ISCOMATRIX(TM) adjuvant, these E6E7 proteins consistently induced E7 specific CTL, in vivo tumor protection, antibody and DTH responses. ISCOMATRIX(TM) adjuvant has been developed for use in the formulation of novel human vaccines and has been evaluated for safety and toxicity in human trials. A formulation containing aluminum hydroxide (Al(OH)(3)) gave a lesser degree of E7 specific antibody, and no local E7 specific CTL response but similar DTH and tumor protection. These findings demonstrate the potential of ISCOMATRIX(TM) adjuvant to stimulate both cellular and humoral immune responses to endogenously processed target antigens, and hence is the preferred adjuvant when CTL responses are desirable. (C) 2004 Elsevier Ltd. All rights reserved.