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ID PMID Title PublicationDate abstract
7535356 Peripheral blood CD5+ B cell subset in the remission phase of systemic connective tissue d 1994 Dec OBJECTIVE: To get a better insight into the level of circulating CD5+ B cells as related to the systemic connective tissue disease activity. METHODS: Peripheral blood CD5+CD19+ cells of patients in the remission phase of systemic lupus erythematosus (SLE) (n = 28), Sjögren's syndrome (SS) (n = 20), rheumatoid arthritis (RA) (n = 26), and 19 control healthy subjects were analyzed by 2-color flow cytometry. RESULTS: In comparison to control group, the patients with SLE had a significant increase in the relative CD19+CD5+ blood cell count (p < 0.0005); this count was also different from the finding in both RA (p < 0.005) and patients with SS (p < 0.05). In contrast, the proportion of B cells expressing CD5 (within an individual B cell population) was significantly increased in all the 3 diseases compared to healthy subjects (SLE, p < 0.0001; SS, p < 0.05; and RA, p < 0.01). In the multivariate discriminant analysis, a discriminant function defined by the CD19+CD5+ subset strongly discriminated SLE, SS and RA from the control, but also SLE from both SS and RA. CONCLUSION: Our findings demonstrated that, in relation to healthy control subjects, the blood CD5+ B subset tended to be elevated in the patients in the remission phase of systemic connective tissue diseases, particularly in SLE.
7935495 Mapping of linear epitopes of human histone H1 recognized by rabbit anti-H1/H5 antisera an 1994 Oct Seventeen synthetic peptides of 15-16 residues, covering the complete sequence of the major human H1b variant, were tested for their capacity to bind serum IgG antibodies from 128 patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (pSS). One peptide (residues 111-127) of the human H1 degree variant and six synthetic and natural fragments of H5 were also tested. Results were compared to those obtained with antibodies from 11 rabbits immunized against chicken H1 and H5, and calf H1. The activity of peptides was tested in direct ELISA and in inhibition assays with free peptides in solution. A major epitope recognized by antibodies from SLE, RA and pSS patients as well as by rabbit antibodies was identified in the C-terminus of H1b (residues 204-218). Other peptides in the globular (residues 79-94) and C-terminal domains of H1b and peptide 111-127 of H1 degree were also recognized, albeit at a lower level and frequency, and some of them contain sequence homologies with peptide 204-218. Patients' antibodies and rabbit antisera were tested with complete H1 proteins from HeLa cells, calf thymus and chicken erythrocytes and with chicken H5. Less than 25% of autoimmune sera contained IgG antibodies reacting with H1/H5 in a direct ELISA. In dot-immunoassay, antigenic activity with intact H1/H5 proteins was detected in a larger number of sera. Using antibodies raised in rabbits against peptides 1-16 and 204-218 of H1b, we found no reaction with H1 immobilized on a solid-phase. In contrast, peptides 144-159, 170-185 and 204-218, which contain identical structural domains, compete with H1 in solution indicating that any of these three regions are accessible at the surface of free H1 and may be involved in the induction of specific antibodies in autoimmune patients.
1333647 [The clinical significance of detecting the inhibition of topoisomerase I by the sera of p 1992 Topoisomerase I activity was studied by electrophoresis in agarose gel according to plasmid DNA relaxation. Sera from 62 patients with systemic scleroderma, 35 with Raynaud's syndrome, 8 with focal scleroderma, 15 with systemic lupus erythematosus, 20 with rheumatoid arthritis and 20 healthy subjects were examined. Out of 62 sera from SSD patients, anti-topoisomerase activity was found in 67.8% of cases. The test appeared positive in 79% of patients with diffuse and 63% with limited disease patterns. The mean age and disease standing were similar in the positive and negative groups. An increase of the skin count and more frequent occurrence of trophic disorders in patients with inhibition of the enzyme were recorded. 40% of the patients demonstrated the coincidence of the results with the use of the topoisomerase test and ELISA. In patients with other rheumatic diseases and in the healthy subjects, no inhibition of the enzyme was found.
8981888 Hybrid primary total hip arthroplasty: a 5- to 9-year followup study. 1996 Dec One hundred fifty-two hips were reviewed at a minimum of 5 years after hybrid primary total hip arthroplasty using uncemented porous coated acetabular components and cemented femoral stems to determine the intermediate term durability of this method of fixation. Five hips (3.6%) have been revised: 1 for dislocation (0.7%), 1 for cup loosening (0.7%), and 3 for femoral loosening (2.2%). Clinical results proved to be extremely reliable in this series with 78% of the patients reporting no pain and 19.7% reporting slight or occasional pain. Radiographic evidence of polyethylene wear was evident in more than 1/2 of cups, but significant osteolysis or component loosening was not commonly seen on the cup side. On the femoral side incomplete radiolucencies were present in 31%, and focal osteolysis in 12.2%, nearly always proximally in Zones 1 and 7. These intermediate term results compare favorably on the femoral side and very favorably on the acetabular side to prior reported series. These results support the continued use of this combination of fixation methods for primary arthroplasty, but polyethylene wear and its effects remain a concern regarding the long term performance of these arthroplasties.
1545661 Stimulus repetition rate effect on the auditory brainstem response in systemic lupus eryth 1992 Mar Neuropsychiatric involvement is common in systemic lupus erythematosus (SLE), but, in early half of cases, indications are not present on examination. Auditory brainstem response (ABR) measures using differential stimulus repetition rates have been reported as sensitive indicators of subclinical central nervous system (CNS) disorders associated with SLE. In the present study, ABRs were measured in a group of normal-hearing subjects with SLE, as well as in a group of subject controls. Differences in interpeak latency (IPL) measures obtained using low- and high-stimulus repetition rates did not reach statistical significance (P greater than .05). Clinical utility of ABRs using high- and low-stimulus repetition rates for the identification of occult CNS disorder in patients with SLE was not demonstrated.
8608632 Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-be 1996 Mar The expression of immunoregulatory cytokines was investigated in freshly isolated synovial fluid mononuclear cells (SFMC) and peripheral blood mononuclear cells (PBMC) from patients with RA, using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. IFN-gamma, TGF-beta, IL-10 and IL-12 (p40) transcripts were detected in SFMC of patients with early disease (<1 year duration) as well as in patients with long standing arthritis (>1 year). The expression of IFN-gamma, IL-10 and IL-12 mRNA was increased in SFMC compared with RA PBMC. In addition, the expression was higher in RA SFMC than in PBMC from health control individuals. Immunoassay analysis of the secreted IL-12 heterodimer demonstrated increased levels in RA SF compared with levels found in serum from RA patients and control individuals. High levels of TGF-beta mRNA were found in SFMC, but a significantly decreased TGF-beta/beta2-microglobulin (beta2-M) ratio was found compared with PBMC from both patients and control individuals. IL-4mRNA could not be detected, either in SFMC or in PBMC. Cytokine expression in RA PBMC did not differ from control PBMC, with the exception of a decreased TGF-beta/beta2-M ratio in RA patients with early disease. Our findings of IFN-gamma mRNA and IL-12, but undetectable levels of IL-4 mRNA, suggest that the synovitis is characterized by a type 1 immune response. The presence of TGF-beta and IL-10 mRNA indicates that immunosuppressive cytokines may also operate in the inflamed joint, although their level of expression may not be sufficient for down-modulation of immune activation.
7607014 [Transposition of the extensor indicis tendon in reconstruction of thumb extension after r 1995 May During a period of 13 years we performed 56 extensor indicis proprius (EIP) transpositions for reconstruction of the ruptured or severed extensor pollicis longus tendon. The open injuries (n = 9) involved failed primary repair or untreated tendon injuries. The subcutaneous ruptures occurred after distal radius fractures (n = 17) or other closed injuries of the wrist (n = 10), without trauma in 14 patients and in 6 patients by rheumatoid synovialitis or collagenosis. 35 patients returned for follow-up examination 8 months to 10.5 years after operation. According to the evaluation scheme suggested by Geldmacher et al. we report 13 excellent, 19 good and 3 satisfactory results. Although several authors prefer EPL reconstruction with an intercalated tendon graft, we recommend the EIP transposition as a simple procedure with predictable satisfactory results.
1371948 The major rheumatoid factor cross-reactive idiotype is dominantly expressed by Staphylococ 1992 Apr Some seropositive (RF+) and seronegative (RF-) rheumatoid arthritis (RA) patients selectively express high concentrations of the major RF cross-reactive idiotype (RCRI) in their sera and generate high frequencies of RCRI+ pokeweed mitogen (PWM)-induced plasma cells from their peripheral blood mononuclear cells (PBM). To determine if normal individuals can express RCRI in vitro, B cells from controls were activated with Staphylococcus aureus Cowan strain I (SAC) bacteria to identify RCRI and RF production. In addition, we studied the relationship of RCRI expression with the subset of B cells bearing CD5. Control CD5+ B cells are responsible for RCRI expression following SAC activation. We also observed that RCRI is dominantly expressed by control SAC-induced B cells in frequencies comparable to that expressed by some RA and juvenile rheumatoid arthritis patients' PBM activated by PWM. Therefore, the frequency of RCRI+ B cells in control and arthritis patients' PBL may be similar, or the selection and/or regulation of RCRI+ B-cell expression in vitro and in vivo may be different in arthritis patients compared to normal individuals.
8222312 Rheumatoid factor production by mononuclear cells derived from different sites of patients 1993 Nov To investigate the origin of circulating rheumatoid factor (RF) and the relation between RF production at different sites in patients with rheumatoid arthritis (RA), mononuclear cells derived from bone marrow, synovium and peripheral blood of patients with RA were examined for the presence of plasma cells and for their capacity to produce RF and other immunoglobulins in vitro. Analysis of culture supernatants for the presence of immunoglobulins demonstrated that cells derived from bone marrow, synovium and peripheral blood were all found to be capable of producing every immunoglobulin and RF isotype investigated. No significant correlations were found between concentrations of immunoglobulin isotypes produced by cells derived from different sites of one individual. Significant correlations were found, however, between concentrations of RF isotypes produced by cells derived from the three sites. These results indicate that the production of RF in the different compartments is not an autonomously regulated process. Mononuclear cells derived from bone marrow were found to be able to produce RF in similar quantities to cells dissociated from synovial tissue. In combination with the fact that circulating immunoglobulins are produced mainly in the bone marrow, this observation suggests that bone marrow is also a major source of circulating RF.
8630101 Enhancement of SPARC (osteonectin) synthesis in arthritic cartilage. Increased levels in s 1996 Apr OBJECTIVE: To investigate the roles of SPARC (secreted protein, acidic and rich in cysteine) (osteonectin) in arthritis, using cartilage and synovium specimens and synovial fluids (SF) from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), and to examine the effects of cytokines, growth factors, and hormones on SPARC synthesis by chondrocytes in culture. METHODS: SPARC in cartilage and synovium was immunostained with monoclonal antibodies. SPARC synthesis by cultured chondrocytes was measured by Northern blot analysis, immunoblotting, and sandwich enzyme-linked immunosorbent assay. RESULTS: SPARC was identified in numerous chondrocytes in the superficial and middle zones and in regenerating chondrocytes of RA and OA joints, whereas such staining was absent in these zones of normal cartilage, except for weak signals from a few chondrocytes in the deep zone. In addition, SPARC synthesis was enhanced in synovial cells of RA and OA joints. The average SPARC level in SF was 10-fold higher in the RA than in the OA population. In rabbit articular chondrocyte cultures, administration of transforming growth factor beta 1 (TGF beta 1) and bone morphogenetic protein 2 increased SPARC levels at 24-48 hours, whereas interleukin-lbeta (IL-1 beta), IL-1 alpha, tumor necrosis factor alpha, lipopolysaccharide, phorbol myristate acetate, basic fibroblast growth factor, and dexamethasone decreased SPARC levels at 24-72 hours. TGF beta increased SPARC messenger RNA (mRNA) levels at 24 hours, whereas IL-1 beta caused a marked decrease in SPARC mRNA levels at 24 hours. Furthermore, IL-1 decreased the glycosylation of SPARC. CONCLUSION: These findings suggest that various growth factors and cytokines, including TGF beta 1 and IL-1 beta, regulate the production of SPARC by chondrocytes at pre- and posttranslational levels, and that SPARC synthesis is markedly enhanced in arthritic joints.
1491853 The Pain Beliefs Questionnaire: an investigation of beliefs in the causes and consequences 1992 Dec This paper reports the development and validation of the Pain Beliefs Questionnaire (PBQ). This is a 20-item questionnaire covering beliefs about the cause and treatment of pain. It was administered to 294 subjects, comprising 100 chronic pain patients and 194 controls. An exploratory factor analysis revealed 2 factors accounting for 68.15% of the variance. From the final solution 2 scales were derived: the first called Organic Beliefs and the second Psychological Beliefs scale, comprising 8 and 4 items, respectively. The construct validity of the questionnaire was assessed in 2 ways. First, the responses of chronic pain patients and non-patient controls were compared: a significant difference (F(1,236) = 53.04, P < 0.0001) between these 2 groups emerged such that chronic pain patients were more likely to endorse the Organic Beliefs scale items, whereas non-patients were more likely to endorse the Psychological Beliefs scale items. Secondly, as predicted significant associations were observed between scores on the Organic Beliefs scale and scores on the Chance and Powerful Others scales of the Multidimensional Health Locus of Control (MHLC), and also between the Psychological Beliefs and Internal scales of the MHLC. No relationship, however, emerged between these scales and measures of pain intensity. The implications of these findings for the assessment and management of chronic pain patients, and in the understanding of the development of chronic pain, are discussed.
7589071 The B lymphocyte in rheumatoid arthritis: analysis of rearranged V kappa genes from B cell 1995 Oct The participation of the humoral immune system in rheumatoid arthritis (RA) is characterized by the production of rheumatoid factors (RF). RF are autoantibodies against the Fc part of IgG which are encoded by diverse germ-line genes. Most of the RF-encoding genes are unmutated, but in RA, a substantial quantity is encoded by somatically mutated genes. In addition, the synovial membranes (SM) of the diseased joints of RA patients are infiltrated by B lymphocytes which form germinal center-like aggregates. To analyze the local immune response, B cell foci from two RA SM were isolated by micromanipulation. From DNA of these foci, the rearranged kappa light chain variable region (V kappa) genes were amplified by polymerase chain reaction (PCR), cloned and sequenced. The amplification of different V kappa-J kappa combinations of different foci suggested oligoclonal expansion of B lymphocytes, which was confirmed by sequence analysis: each PCR product contained members of a single B cell clone. The sequence analysis of 29 different clones revealed rearrangements of diverse V kappa genes. Both frequent representatives of the V kappa 3 and the V kappa 1 family, as well as rarely used genes such as the L10 and B2 genes of the V kappa 2 and V kappa 5 families were found. Of the eleven potentially functional gene rearrangements, eight were significantly mutated, indicating their derivation from antigen-selected B cells. Intraclonal diversity in one of these clones may suggest ongoing mutation in the diseased synovial membrane of patients with RA.
7496926 A confocal microscopy study of anticytoskeletal antibody activity in patients with connect 1994 Jan The significance of the presence of antibodies to cytoskeleton proteins in patients with connective tissue diseases is not clear, as there is a high level of these antibodies in healthy controls. In an attempt to improve the visualization of the immunofluorescence binding pattern of autoantibodies to cytoskeletal structures in cultured fibroblasts, we have used confocal microscopy. Of the 256 serum samples tested, 155 (61%) WERE reactive with cytoplasmic structures. These reactive samples could be divided into seven patterns of binding, as determined by double-blind examination of single-section confocal images. While confirming the results of previous immunofluorescence studies which have shown that autoantibodies that bind to filamentous structures in the cytoplasm of cultured cells are common in patients with connective tissue diseases, we were able to identify three patterns of cytoskeletal binding which may be useful as an adjunct to other tests for the diagnosis of some connective tissue diseases, in particular systemic sclerosis (scleroderma) and rheumatoid arthritis/Sjogren's syndrome. None of the seven patterns was exclusive to a particular disease. We conclude that confocal microscopy may be of limited use as an adjunct to other serological assays in the diagnosis of some forms of connective tissue disease.
8203955 A western blot approach to detection of human plasma protein conjugates derived from D-pen 1994 Apr OBJECTIVES: To develop and apply an immunochemical approach to the study of drug-plasma protein conjugates derived from the anti-arthritic drug D-penicillamine (DP). METHODS: An antiserum with specificity for protein-conjugated DP was raised in a rabbit. Plasma samples from patients receiving DP or from incubations of isolated normal plasma with DP were analysed for DP-derived conjugates by Western blotting using the anti-drug antibody. RESULTS: A single DP-positive protein band was detected in plasma samples from 15/16 patients with rheumatoid arthritis receiving DP but in none of 20 patients of similar disease status who had not taken DP. The positive band appeared in patients' plasma during the course of treatment with DP. It was seen under nonreducing but not reducing conditions indicating that the drug is disulphide linked to the protein. The drug-modified protein migrated to a position intermediate between the trailing edge of albumin and the leading edge of transferrin (both non-reduced) suggesting a molecular weight of between 66 and 77 kDa. Incubations of normal human plasma, but not purified albumin or transferrin, with low concentrations of DP generated the same distinct band plus several less intense DP-positive bands. CONCLUSIONS: Drug-plasma protein conjugates derived from DP in vivo and in vitro can be detected immunochemically by the Western blot method. Theories of DP immunotoxicity have implicated antigenicity of the drug, but this is the first immunochemical demonstration of a potential DP-derived antigen in human plasma. The method we describe may have application to studies of the relationship between DP antigenicity and toxicity.
7688480 Lymphocyte-endothelial interactions in inflamed synovia: involvement of several adhesion m 1993 Aug The role of several adhesion molecules for lymphocyte-endothelial interactions in the synovia of rheumatoid arthritis patients was studied using the frozen section assay. Partial inhibition of lymphocyte binding to endothelium of synovial sections could be observed with antibodies against CD44, L-selectin, and beta 1- and beta 2-integrins, pointing to the participation of several adhesion molecules in the regulation of lymphocyte immigration into inflamed synovia rather than the presence of a unique homing receptor. Different degrees of inhibition were found within a series of antibodies against alpha 4- and beta 1-integrins known to have functional effects in other interaction systems. In addition, increased binding to endothelial cells was induced when lymphocytes were pretreated with TS2/16 anti-beta 1 IgG, whereas binding to non-endothelial components of synovia was increased after treatment with HP 2/4 (anti-alpha 4) Fab. The data suggest a multifunctional role of alpha 4/beta 1-integrins in directly mediating adhesion as well as regulating adhesive interactions in the rheumatoid synovia.
1601643 Interleukin-6 can prime THP-1 macrophages for enhanced production of tumor necrosis factor 1992 Mar Although interferon-gamma has been shown to effectively prime macrophages for enhanced production of tumor necrosis factor-alpha (TNF alpha), it is reasonable to assume that other cytokines present in the extracellular environment may likewise facilitate cytokine biosynthesis. For example, interleukin-6 (IL-6) is synthesized by synovial lining macrophages and fibroblasts, and has been detected (along with TNF alpha) in rheumatoid synovial effusions. Therefore, the purpose of the present study was to determine whether IL-6 influences the production of IL-1 beta and/or TNF alpha by THP-1 macrophages. Although IL-6 treatment alone resulted in only a slight increase in TNF alpha levels, administration of IL-6 followed by Sal. minnesota LPS resulted in a synergistic potentiation of TNF alpha production by THP-1 macrophages. The priming effect of IL-6 could be reversed by boiling, or by the addition of a neutralizing polyclonal antibody against IL-6. Notably, IL-6 only weakly enhanced interleukin-1 beta production. In summary, the ability of IL-6 to potentiate TNF alpha production by THP-1 macrophages may provide insight into the regulation of the cytokine network in inflammatory diseases, such as rheumatoid arthritis.
7911833 Influence of corticosteroid pulse therapy on the serum levels of soluble interleukin 2 rec 1994 Mar OBJECTIVE: To investigate the influence of corticosteroid pulse (CP) therapy on soluble interleukin 2 receptor (sIL-2R), interleukin 6 (IL-6) and IL-8 levels in patients with active rheumatoid arthritis (RA). METHODS: Twenty-five patients with active RA were studied before and after treatment with intravenous CP therapy. In 12 patients lymphocyte subsets were also assessed. RESULTS: All patients showed a significant decrease in clinical disease activity variables after 4 to 8 weeks of CP therapy. Baseline levels of sIL-2R were higher among patients with active RA than healthy controls; after CP therapy, sIL-2R levels decreased significantly, but not as much as the erythrocyte sedimentation rate or C-reactive protein. In most cases baseline levels of both IL-6 (n = 23) and IL-8 (n = 17) could be measured and both decreased significantly after CP therapy. Cortisol levels were suppressed shortly after CP therapy but had returned to pretreatment values at 4 weeks. After CP therapy there was a temporary increase in the number of HLA-DR positive cells and a decrease in the number of CD3 positive cells, while the CD4/CD8 ratio and IL-2 receptor (CD25) positive cells remained unchanged. CONCLUSION: High dose corticosteroids influence serum levels of sIL-2R, IL-6 and IL-8 in patients with active RA.
7510810 Choroidal infiltrates as the initial manifestation of lymphoma in rheumatoid arthritis aft 1994 Mar OBJECTIVE: To report the third known and documented occurrence of malignant disease as a complication of immunosuppression associated with low-dose methotrexate therapy for rheumatoid arthritis. MATERIAL AND METHODS: We present a case report of a 64-year-old woman with rheumatoid arthritis who had received low-dose methotrexate therapy for 16 months in whom blurred vision occurred. An ophthalmologic examination was performed, and prednisone was administered. Subsequently, she complained of sore throat, weakness, and fever. An axillary lymph node biopsy and immunologic studies were done. RESULTS: Funduscopic examination revealed severe bilateral choroidal thickening. Findings on the biopsy disclosed a large cell, B-cell phenotype non-Hodgkin's lymphoma. Immunologic studies performed on frozen and paraffin-embedded tissue samples showed that the neoplastic cells were positive for CD20 and CD22 and without definite immunoglobulin light chain expression. CONCLUSION: Although the occurrence of lymphoma may be associated with autoimmune diseases, low-dose methotrexate therapy has also been implicated. Because of the increasing use of low-dose methotrexate therapy for classic and juvenile rheumatoid arthritis, an increased risk of lymphoproliferative disease is possible.
8235292 Studies on the expression of the TNF alpha receptors (p55 and p75) and their relative cont 1993 The effect of monoclonal antibodies against the 55- and 75-kDa (p55 and p75) tumour necrosis factor (TNF) receptors on two tumour necrosis factor alpha (TNF alpha) induced responses was studied in rheumatoid synovial fibroblasts (RSF) in vitro. This provided functional evidence for the expression of both receptor types, which was confirmed by substantial inhibition of 125I-TNF alpha binding to RSF by both antibodies. TNF alpha stimulation of prostanoid production was found to be a function of ligand binding to both receptor types, whereas the stimulation of cellular glycolysis was largely mediated via the p55 receptor. Thus, we showed that RSF express both types of TNF receptor and functional studies showed that stimulation of each receptor results in both similar and dissimilar cellular responses.
7805704 Rheumatic diseases--clinical experience with piroxicam-beta-cyclodextrin. 1993 The clinical relevance of piroxicam-beta-cyclodextrin (PBC) in the long-term treatment of osteoarthritis and rheumatoid arthritis is reviewed. Two hundred and twenty-five patients--one hundred with rheumatoid arthritis and one hundred and twenty five with osteoarthritis--were enrolled in a double-blind, randomised, controlled study versus piroxicam. Drugs were administered once-daily, for twelve weeks. The indices of efficacy (pain intensity, severity of inflammation, functional impairment evaluated at 0,2,4,8 and 12 weeks showed the good analgesic effect of piroxicam without significant differences between its two formulations. Tolerance appeared to be better in the group of patients treated with PBC than in the one treated with piroxicam. Both the incidence and severity of side effects were lower for patients treated with PBC. The majority of side effects were related to the gastrointestinal tract. The study suggests that PBC, used in the long term treatment of rheumatic diseases, improves the safety of piroxicam without affecting its efficacy. In another study, thirty patients with chronic osteoarthritis were randomly assigned to receive PBC or tenoxicam daily for eight weeks. Both drugs effectively reduced pain, inflammation, and functional limitation of the affected joints. Endoscopy revealed minor post-treatment mucosal lesions; these tended to be less severe with PBC than with tenoxicam. The clinical experience in the long-term treatment of rheumatic conditions indicates that the microencapsulation of piroxicam as piroxicam-beta-cyclodextrin has provided a new drug with a superior tolerability compared to the parent compound without affecting its high efficacy on the symptoms of the primary disease.