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Seminars in Arthritis and Rheumatism
Volume 23, Issue 6, Supplement 2,
, Pages 44-49
Immunomodulators represent a unique class of drugs that are not biologics, usually are isolated from nature, and have relatively specific noncytotoxic effects on the immune system. Although most slow-acting antirheumatic drugs (SAARDs) have effects on the immune system, these effects usually are not specific, often are cytotoxic, are not associated with specific cellular binding proteins, and their effect on immunity is difficult to correlate with their clinical effects. Most immunomodulators primarily affect T cells; because of their apparent role in rheumatoid arthritis (RA), studies of these agents are appropriate. Cyclo-sporine, the most widely tested of the immunomodulators, has shown significant efficacy in established RA in studies worldwide. However, only one study using cyclosporine has been performed in relatively early RA, in which the most positive effects might be expected. FK506 and rapamycin, agents similar to cyclosporine, are being tested in human transplantation; the only arthritis studies have been performed in animals. Tilomisole, imuthiol, and mycophenolate mofetil have been studied in limited RA trials, with positive effects. However, no trials have been conducted in early RA. Although promising, this class of drugs will require more studies to establish their efficacy and safety, especially in early RA.
- G Renoux et al.Involvement of brain neocortex and liver in the regulation of T cells: The mode of action of sodium diethyldithiocarbamate (imuthiol)
(1984)(Video) Evaluating drug-free remission with abatacept in early rheumatoid arthritis
- SC Gilman et al.Immunological abnormalities in rats with adjuvant-induced arthritis. II. Effect of antiarthritic therapy on immune function in relation to disease involvement
Int J Immunopharmacol
- DE YocumCyclosporine in rheumatoid arthritis, Beyond experimentation
- H Miyahara et al.Comparative studies of the effects of FK 506 and cyclosporin A on passively transferred collagen-induced arthritis in rats
Clin Immunol Immunopath
- P Tugwell et al.Low-dose cyclosporine versus placebo in patients with rheumatoid arthritis
- JS Hyams et al.Cyclosporine treatment of auto-immune chronic active hepatitis
- RB Nussenblatt et al.Cyclosporine A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents
Am J Ophthalmol
- CS Lin et al.FK-506 and cyclosporin A inhibit highly similar signal transduction pathways in human T lymphocytes
- RL Wilder et al.
Mechanisms of bone and cartilage destruction in rheumatoid arthritis: Lessons from the streptococcal cell wall arthritis model in LEW/N rats
Clin Exp Rheumatol
- NH Sigal et al.
Cyclosporin A FK-506, and rapamycin: Pharmacologic probes of lymphocyte signal transduction
Annu Rev Immunol
Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription
Inhibition of T and B lymphocyte proliferation by rapamycin
Immunosuppressive effects of cyclosporin A on cloned T cells
In situ hybridization for interleukin 2 and interleukin 2 receptor mRNA in T cells activated in the presence or absence of cyclosporin A.
J Exp Med
The immunosuppressant FK-506 selectively inhibits expression of early T cell activation genes
Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK-506 or rapamycin
Inhibition of the immune response by rapamycin: a new antifungal antibiotic
Can J Physiol Pharmacol
Suppression of Bcell activation by cyclosporine A, FK506 and rapamycin
Eur J Immunol
The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T-cells
Synergistic interactions of cyclosporine and rapamycin to inhibit immune performances of normal human peripheral blood lymphocytes in vitro
Cyclosporine A in severe treatment-refractory rheumatoid arthritis: A randomized study
Ann Intern Med
Cyclosporine improves psoriasis in a double-blind study
Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset: Results of a multi-center doubleblind trial
A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis
N Engl J Med
Preliminary results of a double-blind, randomized, placebo controlled trial of cyclosporine in myasthenia gravis
N Engl J Med
Cyclosporin treatment for rheumatoid arthritis: A placebo-controlled double-blind multi-center study
Ann Rheum Dis
Cyclosporine in rheumatoid arthritis. A double-blind, placebo controlled study in 52 patients
Ann Rheum Dis
Inhibition by cyclosporin A of streptococcal cell-wall-induced arthritis and hepatic granulomas in rats
- Suppressive effects of bee venom on the immune responses in collagen-induced arthritis in rats
The effect of bee venom (BVA) on the development of type II collagen (CII)-induced arthritis (CIA) in rats has been studied. Male rats were immunized with an emulsion of 200μg of CII and complete Freund's adjuvant (CFA). The rats were then given intraperitoneally (i.p.) injection of a suspension of BVA or saline during the experiment. The effect of BVA on cellular responses to CII was examined. In the control rats, the onset of arthritis was observed at the 24th day after the CII-immunization, and the severity of CIA was developed gradually. As compared with rats treated with saline, BVA i.p. injected at doses of more than 20μl/100g mouse once a day for 14 days inhibited the ability of inguinal lymph node cells to produce T cell cytokines interleukin-1β, -2, -6, tumor necrosis factor-α and interferon-γ when the cells were obtained from rats 24 days after immunization and cultured in vitro with CII. When rats were injected i.p. with sheep red blood cells, hemagglutination titers in BVA-treated and control rats did not differ significantly when low doses of BVA was given to rats. However, i.p. injection of BVA at doses of more than 10μl/100g/day suppressed antibody production. Pretreatment of rats with BVA could inhibit the development of collagen arthritis even when 10–20μl/100g/day of the BVA were used for pretreatment. Interestingly, higher doses than 10μlBVA/100g mouse were much effective for arthritis incidence. Treatment of rats with BVA prevented the development of collagen arthritis in a dose-dependent manner. Doses of BVA (15 and 20μl/100g) resulted in decreased incidence of arthritis. In conclusion, therapeutic i.p injection with BVA improved the clinical course of the disease and the immune response to CII.
- Inhibitory effect of Buthus martensi Karsch extracts on interleukin-1β-induced expression of nitric oxide (NO) synthase and production of NO in human chondrocytes and LPS-induced NO and prostaglandin E2 production in mouse peritoneal macrophages
2005, Toxicology in Vitro
We examined the effect of Buthus martensi Karsch (BMK) extract on IL-1β-induced production of nitrogen oxide (NO) in primary human osteoarthritis (OA) chondrocytes. The cells were treated with BMK (10μg/ml) and IL-1β (2ng/ml) for different periods, and inducible nitric oxide synthase (iNOS) mRNA and protein expression were determined by real-time quantitative reverse transcriptase–polymerase chain reaction and Western blotting, respectively. The cytotoxicity of BMK on human OA chondrocytes was very low (IC50>250μg/ml) as measured by the XTT assay method. Production of NO was determined as nitrite in culture supernatant. Human chondrocytes cotreated with BMK produced significantly less NO compared with chondrocytes stimulated with IL-1β alone. Activation and translocation of and NF-κB DNA binding activity were determined by Western blotting and specific enzyme-linked immunosorbent assay. The inhibition of NO production correlated with the suppression of induction and expression of nuclear factor-κB (NF-κB) and activation protein-1 (AP-1)-dependent gene. BMK inhibited the activation and translocation of NF-κB to the nucleus, indicating that BMK inhibits the IL-1β-induced production of NO in human chondrocytes by interfering with the activation of NF-κB through a novel mechanism. In addition, BMK reduced prostaglandin E2 (PGE2) production in mouse peritoneal macrophages stimulated with lipopolysaccharide, whereas no influence on the activity of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) or cyclooxygenase-1 (COX-1) was observed. Our data, therefore, suggest that BMK may be a therapeutically effective inhibitor of IL-1β-induced inflammatory effects that are dependent on NF-κB activation in human OA chondrocytes. The results indicate that BMK exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and PGE2 production, which could be due to a decreased expression of iNOS and COX-2 through the transcription factors NF-κB and AP-1.
- Effect of bee venom on aromatase expression and activity in leukaemic FLG 29.1 and primary osteoblastic cells
2005, Journal of Ethnopharmacology
The effect of bee venom aqua-acupunture (BVA) (api-toxin), a traditional immunosuppressive Korean aqua-acupuncture, on the bone function in human osteoblastic cells was studied. To provide insights into the effect of BVA on aromatase activity in bone-derived cells, we examined the human leukaemic cell line FLG 29.1, which is induced to differentiate toward the osteoclastic phenotype by TPA and TGF-β1, and the primary first-passage osteoblastic cells (hOB). Southern blot of RT-PCR products with a 32P-labeled cDNA probe for the human aromatase demonstrated that FLG 29.1 and hOB cells express aromatase mRNA. Gene expression and enzyme activity were stimulated in a time-dependent fashion by 5.0μl/ml BV and by either 1–50nM TPA or 0.01–0.5ng/ml TGF-β1, with maximal responses after 2–3h exposure. After 24h incubation of the cells in the absence of these stimuli the aromatase mRNA and the protein were barely detectable. These findings demonstrate that cells of the osteoclastic lineage synthesize aromatase in vitro by the local cytokine of TGF-β1 and BVA. These can offer an explanation for the lack of development of osteoarthritis in BVA-treated patients.
- Mycophenolate mofetil, Cellcept®, a new immunosuppressive drug with great potential in internal medicine
2000, Netherlands Journal of Medicine(Video) Therapy of RA with Non-Biologic DMARDs -- ep. 21 of 32
Mycophenolate mofetil is a new immunosupressive drug, exhibiting its effect through inhibition of proliferation of T- and B-lymphocytes. Superior efficacy of mycophenolate mofetil compared to azathioprine, in combination with cyclosporine and prednisone, in the prevention of acute rejection in organ transplantation has made mycophenolate mofetil one of the standard immunosupressive drugs after transplantation. Mycophenolate mofetil also is an interesting candidate drug for many other, mainly auto-immune mediated diseases. The use of mycophenolate mofetil in several of these diseases is discussed. The definitive place of mycophenolate mofetil will depend on the results of randomised trials currently under way.
- Suppressive effects of Tripterygium wilfordii Hook f., a traditional Chinese medicine, on collagen arthritis in mice
The effect of chloroform extract of Tripterygium wilfordii Hook f. (TWH extract), a traditional immunosuppressive Chinese herb, on type II collagen (C II)-induced arthritis (CIA) in DBA/1J mice was studied. In the first set of experiments, we examined the effect of TWH extract on cellular immune responses to C II. As compared with mice treated with saline, TWH extract administered orally at doses of more than 400 μg kg−1 once a day for 14 days inhibited the ability of inguinal lymph node cells to produce T cell cytokines interleukin-2 and interferon-γ when the cells were obtained from mice 21 days after immunization and cultured in vitro with C II. Treatment with TWH extract also inhibited production of macrophage cytokines interleukin-1β and tumor necrosis factor-α in response to in vitro stimulation of lymph node cells with C II. In the second part of the experiment, we evaluated the influence of TWH extract on the incidence and development of arthritis in murine CIA. Mice were immunized twice at a 3-week interval with bovine C II, with TWH extract being given orally once a day for 14 days with four different regimens. A 14-day course of TWH extract treatment at a daily dose of 400 μg kg−1, which began on the day of the first C II immunization, suppressed the development of arthritis, as well as antibody production and delayed-type hypersensitivity to C II. Treatment with TWH extract, which started on the same day as the booster immunization, also resulted in inhibition of development of arthritis and of immune responses to C II. On the other hand, therapeutic administration with TWH extract did not affect the clinical course of the disease and the immune response to C II.
- Effects of antirheumatic agents on cytokines
1996, Seminars in Arthritis and Rheumatism
A review of the literature concerning the effects of traditional antirheumaticdrugs on cytokines and the cytokine and anticytokine approaches already used in the therapy of rheumatoid arthritis (RA) is presented. Many antirheumatic drugs are capable of cytokine modulation in vitro. Corticosteroids inhibit the transcription of a broad spectrum of genes including those encoding monocyte, T cell-derived cytokines and several hemopoietic growth factors, whereas drugs such as cyclosporin A and d -penicillamine interfere with T cell activation more specifically by suppressing i,nterleukin 2 (IL-2) production. The in vivo effects of drug therapy on cytokines in RA patients are less well established. Gold compounds reduce circulating IL-6 levels and the expression of monocyte- derived cytokines, such as IL-1, tumor necrosis factor (TNF), and IL-6, in the rheumatoid synovium. Decreases in circulating IL-6, soluble IL-2 (sIL-2R), and TNF receptors and in synovial fluid IL-1 levels have been reported with methotrexate. Reductions in circulating IL-6 and sIL-2R concentrations have also been observed with cyclosporin and corticosteroids, whereas azathioprine reduces IL-6 but not sIL-2R. Studies on sulfasalazine are conflicting and the in vivo effects of D-penicillamine and antimalarials have not been studied yet. Interferon γ therapy is not effective in RA but may prove a useful antifibrotic for systemic sclerosis. Colony stimulating factors improve the granulocytopenia associated with Felty's syndrome or drug toxicities but can induce arthritis flares and should be reserved to treat infectious complications. Promising results are being obtained with selective antagonism of TNF and IL-1 in RA, and combinations of anticytokine strategies with traditional antirheumatic drugs have been already envisaged. These should preferably be based in a broader knowledge of the effects of antirheumatic agents on the cytokine network.
Research articleAntenatal fibrinogen concentrations and postpartum haemorrhage
International Journal of Obstetric Anesthesia, Volume 23, Issue 4, 2014, pp. 365-370
It is unclear whether antenatal fibrinogen concentrations are associated with postpartum haemorrhage.
This retrospective study included 871 women with a singleton pregnancy but no known risk factors for postpartum haemorrhage, in whom fibrinogen concentration was measured within the 21days before delivery. Correlation between antenatal fibrinogen concentrations and estimated blood loss was analysed. We tested the hypothesis that the risk of postpartum haemorrhage was higher in women with antenatal fibrinogen concentrations of <3.3g/L. Postpartum haemorrhage was defined as an estimated blood loss ⩾700mL following vaginal delivery and ⩾1000mL following caesarean delivery.
In women delivering vaginally (n=337), estimated blood loss tended to increase with decreasing antenatal fibrinogen concentration (R=−0.107, P=0.05), median fibrinogen concentration was significantly lower in 69 women with postpartum haemorrhage than in 268 women without postpartum haemorrhage (3.93 vs. 4.18g/L, P=0.025), and postpartum haemorrhage occurred significantly more often in women with fibrinogen concentrations <3.3g/L than in those with concentrations ⩾3.3g/L (38% [11/29] vs. 19% [58/308], P=0.018). In women undergoing caesarean delivery (n=534), median fibrinogen concentration did not differ between those who experienced postpartum haemorrhage (n=128) and those who did not (n=406) (4.18g/L vs. 4.07g/L, P=0.43). Antenatal fibrinogen concentrations of <3.3g/L were not associated with higher rates of postpartum haemorrhage (26% [11/43] vs. 24% [117/491], P=0.80).
Antenatal fibrinogen concentration <3.3g/L may be a risk factor for postpartum haemorrhage among women following vaginal delivery.
Research articleThermolysis of 1-(thiophen-2-yl)-1H-tetrazoles: a route to thiophene-fused imidazoles and pyrimidines
Tetrahedron, Volume 71, Issue 21, 2015, pp. 3343-3350
Thermal reactions of 1-(thiophene-2-yl)-1H-tetrazoles are reported for the first time. The solution thermolysis of 1-(thiophene-2-yl)-1H-tetrazoles under conventional heating and microwave irradiation afforded the unexpected new thieno[2,3-d]pyrimidines incorporating two thiophene rings, which were obtained as major or only product. The synthesis of these heterocycles was rationalized considering the initial nitrogen elimination to generate imidoylnitrene followed by rearrangement to the corresponding carbodiimide and subsequent cyclization triggered by the nucleophilic attack of the in situ generated 2-aminothiophene. The flash vacuum pyrolysis and solution thermolysis of 1-(thiophene-2-yl)-1H-tetrazoles also gave thieno[2,3-d]imidazoles via intramolecular formal insertion into a C–C bond of the corresponding imidoylnitrene intermediate.(Video) TEAR Trial for Early Aggressive Rheumatoid Arthritis
Research articleComputational study of the structures and photoelectron spectra of gas-phase nitrosamines: Dimethylnitrosamine, N-nitrosopyrrolidine and 1-nitrosoaziridine
Journal of Electron Spectroscopy and Related Phenomena, Volume 232, 2019, pp. 35-39
The structures of three nitrosamines in gas phase are optimized with various levels of theory available in the Gaussian program. For dimethylnitrosamine and N-nitrosopyrrolidine, the reported rotational constants from microwave spectra let us select the best optimized geometry. For 1-nitrosoaziridine, however, we decide to choose the geometry optimized by CCSD/cc-pVTZ method. At these geometries, the photoelectron spectra are calculated with established methods using the Amsterdam Density Functional program. The calculated ionization energies of valence electrons agree well with available experimental data and provide values for the missing photoelectron data. On the other hand, the computed core-electron binding energies of dimethylnitrosamine agree well with the values from 1975 X-ray solid-state photoelectron spectra after adding the work function. The predicted values for N-nitrosopyrrolidine and 1-nitrosoaziridine must wait for experiments for confirmation.
Research articleA novel mutation in the JH4 domain of JAK3 causing severe combined immunodeficiency complicated by vertebral osteomyelitis
Clinical Immunology, Volume 183, 2017, pp. 198-200
JAK3 is a tyrosine kinase essential for signaling downstream of the common gamma chain subunit shared by multiple cytokine receptors. JAK3 deficiency results in T−B+NK− severe combined immune deficiency (SCID). We report a patient with SCID due to a novel mutation in the JAK3 JH4 domain. The function of the JH4 domain remains unknown. This is the first report of a missense mutation in the JAK3 JH4 domain, thereby demonstrating the importance of the JH4 domain of JAK3 in host immunity.
Research article2.20 Selected Diastereoselective Reactions: Ionic and Zwitterionic Cyclizations
Comprehensive Chirality, Volume 2, 2012, pp. 607-624
The development of new synthetic methods for the formation of carbon–carbon bonds is of paramount importance for the efficient synthesis of molecules having important applications in medicine, material science, biofuels, etc. In the past decade, ionic cyclizations have regained popularity as a strategy of choice to construct polycyclic structures. One can argue that this could be due to a better mechanistic understanding helping to predict the stereochemical outcome of the reaction. Also, one cannot ignore that the development of new efficient catalysts has made several ionic cyclizations more adaptable in the context of total synthesis. In fact, several catalytic ionic cyclizations reported in the literature have demonstrated the power and the usefulness of these processes in organic synthesis. In this chapter, the authors selected recent examples to outline the progress made in the field.
Research articleProfound bilateral post-partum retinal circulation ischemia in two diabetic mothers with pre-eclampsia
American Journal of Ophthalmology Case Reports, Volume 13, 2019, pp. 28-31
We report 2 cases of young diabetic mothers with pre-eclampsia and no previously documented visual deficits prior to pregnancy who were found to have profound retinal circulation loss during the postpartum period.
Fluorescein angiogram in both cases documented profound ischemia of retinal and macular circulation with resulting severe vision loss, leading to legal blindness.
While Pre-eclampsia and Eclampsia are well known clinical entities with potentially grave effects on both the mother and child, there is little information about the possible combined effects of diabetes and Pre-eclampsia/Eclampsia on the retinal circulation. We aim to raise awareness about this devastating association with a need for aggressive monitoring and prompt treatment of similar patients to potentially avoid poor visual outcomes.
Copyright © 1994 Published by Elsevier Inc.
Cyclosporine, the most widely tested of the immunomodulators, has shown significant efficacy in established RA in studies worldwide.
Immunomodulators are a group of drugs that mainly target the pathways that treat multiple myeloma and a few other cancers. They have many ways to work, including working on the immune system directly by turning down some proteins and turning up others.
Immunomodulation is a key issue in tissue homeostasis for the physiological stability of organisms. Consequently, it is important to search for immunoregulators, such as those derived from natural immunomodulators, with less severe side effects.
Official answer. The newest drugs for the treatment of rheumatoid arthritis are the Janus kinase (JAK) inhibitors, which are FDA approved under the brand names Rinvoq, Olumiant, and Xeljanz.