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Bucillamine, a unique anti-rheumatic drug
Abstract
Bucillamine (N-(2-mercapto-2-methylpropionyl)-L-cysteine), an antirheumatic drug, is used clinically in Japan and in Korea primarily to treat patients with rheumatoid arthritis (RA). Bucillamine has structural similarities to D-penicillamine, but contains two free sulfhydryl groups, resulting in molecular and therapeutic effects significantly different from D-penicillamine. Bucillamine appears to be more effective in treating RA than D-penicillamine. Bucillamine has been characterized as an immunomodulatory agent with suppressive effects on various B and T cell functions. In clinical use for RA, bucillamine attenuates rheumatoid factor titers, erythrocyte sedimentation rates, and C-reactive protein levels. These actions suggest bucillamine has anti-inflammatory and immunomodulatory effects in cases of RA. However, the details of bucillamine's antirheumatic mechanism with respect to its effects in RA therapy remain unknown. Our review discuses bucillamine's antirheumatic mechanism, based primarily on previously published reports. It is our hope that bucillamine will eventually benefit a broader range of RA patients.
To identify the molecular mechanisms of bucillamine activity, global gene expression analysis and pathway analysis were conducted using IL-1 beta-stimulated human fibroblast-like synovial cells (FLS).
Normal human FLS were treated with IL-1 beta in the presence or absence of 10 and 100 microM bucillamine for 6 h. Total RNA was extracted and global gene expression levels were detected using a 44 k human whole genome array. Data were analyzed using Ingenuity pathway analysis.
Numerous pathways were activated by IL-1 beta stimulation. At both concentrations, bucillamine suppressed nine signal pathways stimulated by IL-1 beta.
Bucillamine effectively inhibited fibroblast growth factor (FGF) signaling and tight junction signaling activated by IL-1 beta in FLS. Suppression of these signal pathways may correlate with the pharmacologic mechanisms of bucillamine. In particular, the suppression of FGF signaling by bucillamine is remarkable because the activation of FGF signaling may be involved in rheumatoid arthritis pathology.
Finding a means to ameliorate and prevent bone destruction is one of the urgent issues in the treatment of rheumatoid arthritis. Recent studies revealed bone-resorbing osteoclasts to be essential for arthritic bone destruction, but to date there has been scarce experimental evidence for the underlying mechanism of the bone-protective effect of antirheumatic drugs. Here we examined the effects of one or a combination of disease-modifying antirheumatic drugs (DMARDs) on osteoclast differentiation to provide a cellular and molecular basis for their efficacy against bone destruction. The effects on osteoclast precursor cells and osteoclastogenesis-supporting cells were distinguished by two in vitro osteoclast culture systems. Methotrexate (MTX), bucillamine (Buc) and salazosulphapyridine (SASP) inhibited osteoclastogenesis by acting on osteoclast precursor cells and interfering with receptor activator of NF-kappaB ligand (RANKL)-mediated induction of the nuclear factor of activated T cells (NFAT) c1. MTX and SASP also suppressed RANKL expression on osteoclastogenesis-supporting mesenchymal cells. Interestingly, the combination of three antirheumatic drugs exerted a marked inhibitory effect on osteoclastogenesis even at a low dose at which there was much less of an effect when administered individually. These results are consistent with the reported efficacy of combined DMARDs therapy in humans and suggest that osteoclast culture systems are useful tools to provide an experimental basis for the bone-protective effects of antirheumatic drugs.
We investigated the bucillamine (Buc) mechanism inhibiting interleukin (IL)-1beta-induced vascular endothelial growth factor (VEGF) production from human fibroblast-like synoviocytes (HFLS) which derived from the inflamed synovium of an RA patient using SA981, its active metabolite. HFLS did not produce IL-1beta, spontaneously. While SA981 partially inhibited IL-1beta-induced VEGF production at concentrations of 10 to 100 microM (10.1% and 14.2% inhibition of total VEGF production under IL-1beta coexistence condition, respectively), it failed to inhibit IL-1beta-induced IL-6 production at the same concentrations. IL-1beta induced phosphorylation of the mitogen-activated protein (MAP) kinases, IkappaBalpha, c-Jun and Akt. SA981 at a concentration of 100 microM partially inhibited IL-1beta-induced phosphorylation of p38MAPK and Akt (12.0% and 36.1% inhibition of each total amount of phosphoprotein under IL-1beta coexistence condition, respectively). The VEGF promoter includes four transcription factors: AP1, hypoxia-inducible factor (HIF), Sp1 and AP2 binding elements. HIF-1beta, Sp1 and AP1 increased under IL-1beta coexistence conditions. At a concentration of 100 microM, SA981 attenuated increases in HIF-1beta and Sp1 (10.1% and 19.8% inhibition of each total amount of transcription factor under IL-1beta coexistence condition, respectively), but not AP1. These results suggest that SA981 partially inhibits VEGF production via modifications on IL-1beta signaling. Attenuation of the expression of HIF-1beta and Sp1 (but not AP1) may be a key with respect to SA981's selective inhibition of VEGF production.
Although several epidemiological studies indicate a correlation between exposure to ambient particulate matter and adverse health effects in humans, there is still a fundamental lack of understanding of the mechanisms involved. We set out to test the hypothesis that reactive oxygen species are involved in the adjuvant effects of diesel exhaust particles (DEP) in a murine OVA sensitization model. First, we tested six different antioxidants, N-acetylcysteine (NAC), bucillamine (BUC), silibinin, luteolin, trolox (vitamin E), and ascorbic acid, for their ability to interfere in DEP-mediated oxidative stress in vitro. Of the six agents tested, only the thiol antioxidants, BUC and NAC, were effective at preventing a decrease in intracellular reduced glutathione:glutathione disulfide ratios, protecting cells from protein and lipid oxidation, and preventing heme oxygenase 1 expression. Therefore, we selected the thiol antioxidants for testing in the murine OVA inhalation sensitization model. Our data demonstrate that NAC and BUC effectively inhibited the adjuvant effects of DEP in the induction of OVA-specific IgE and IgG1 production. Furthermore, NAC and BUC prevented the generation of lipid peroxidation and protein oxidation in the lungs of OVA- plus DEP-exposed animals. These findings indicate that NAC and BUC are capable of preventing the adjuvant effects of inhaled DEP and suggest that oxidative stress is a key mechanistic component in the adjuvant effect of DEP. Antioxidant treatment strategies may therefore serve to alleviate allergic inflammation and may provide a rational basis for treating the contribution of particulate matter to asthmatic disease.
Efficacy of combination therapy for polyarthritis was studied using MRL/I mice. Salazosulfapyridine (SASP), bucillamine (Bc), and methotrexate (MTX) were employed. The agents were given to the mice in either single- drug administration, else two-drug or three drug combination therapy. Single drug administration in lowered dose had no beneficial effect on the joint lesions. The two-drug combination, SASP + MTX and Bc + MTX, had efficacy in suppressing fibroblast proliferation in the periarticular soft tissue. The three drug combination, SASP + Bc + MTX, had remarkable effects on the lesions, suppressing multiplication of synovial lining cells, subsynovial soft-tissue oedema bone/cartilage replaced by connective tissue, fibrin exudation, fibroblast proliferation, and pannus formation, with statistical significance. When the efficacy of the optimum dose of the respective drugs was compared with the results of combination therapy, three drug combinations gained new effects, which were not identified as additive or synergistic. The mode of action of the combination therapy remains to be elucidated. In Chinese herbal medicine, numerous combinations provide different clinical indications respectively. Such evidence introduces the concept of polypharmacology, which is a reasonable scientific term for studying combination therapy further.
Bucillamine is a new disease-modifying antirheumatic drug (DMARD) that was developed in Japan, where it is widely used in clinical practice. However, there is no published information concerning the use of bucillamine in patients from countries other than Japan. This preliminary study was designed to assess the clinical efficacy and tolerability of bucillamine in Korean patients with rheumatoid arthritis. Patients were treated with bucillamine 300 mg/day for 16 weeks. Clinical efficacy was demonstrated by improvement in the Ritchie index, number of painful joints, number of swollen joints, duration of morning stiffness, walking time and erythrocyte sedimentation rate (ESR); these improvements generally became statistically significant by week 8 of treatment. There were also improvements in rheumatoid factor titre and C-reactive protein levels. The rate of final global improvement was 73%. The most frequent adverse effects were mucocutaneous signs, which were generally mild and usually resolved with symptomatic treatment despite continuation ofbucillamine therapy. Bucillamine is expected to be a useful DMARD for the treatment of rheumatoid arthritis, and further large-scale, long term clinical trials, particularly comparing bucillamine with penicillamine, are warranted.
This study was designed to ascertain some nutrition and nutrition related social factors in the environment of the child with anemia. In this study, it was found that the child with iron deficiency anemia consumed less iron per kilogram per day, drank more milk, was less likely to have been given supplemental iron, was introduced to strained foods at an older age, and had a greater number of siblings. The mother was more likely to be separated or divorced, view the child as having more feeding problems and be an inappropriate weight for age, have somewhat different expectations of his ability to perform certain tasks, and be, in general, less satisfied with the child. The family group spent less per capita on food and cared for the child in the home more of the time. A better understanding of these factors, important in the development of iron deficiency anemia, may eventually lead to amelioration of the problem.
We investigated the ability of bucillamine [N-(2-mercapto-2-methyl-propionyl)-L-cysteine] to prevent T cell adhesion to endothelial cells (EC) isolated from human umbilical vein. When EC were pretreated with bucillamine, T cell binding to the EC was suppressed in a dose dependent fashion. The T cells could bind preferentially to recombinant interferon-gamma (rIFN-gamma) treated EC compared with untreated EC. Bucillamine could also suppress T cell binding to rIFN-gamma treated EC as well as untreated EC. Addition of copper sulfate to bucillamine decreased significantly the percent T cell adhesion to the EC compared with bucillamine alone. The magnitude of inhibition by bucillamine and copper sulfate was similar in EC treated with rIFN-gamma as well as in untreated EC. H2O2 also inhibited the T cell binding to both untreated and rIFN-gamma treated EC. The inhibitory effects of bucillamine with or without copper sulfate on T cell binding to EC were abolished completely by catalase but not by superoxide dismutase. Our results suggest that hydrogen peroxide generated by bucillamine, with or without copper sulfate, inhibits T cell binding to EC. We believe, therefore, that bucillamine may suppress inflammation, such as that in rheumatoid synovitis, by reducing the emigration of chronic inflammatory cells from capillaries into tissue.
The effects of bucillamine, a new antirheumatic drug, on type II collagen induced arthritis in rats was examined. Bucillamine inhibited hindpaw swelling in a dose dependent manner. The histopathological study indicated that bucillamine inhibited the proliferation of synovial lining cells. The anti-type II collagen antibody level was also decreased by the treatment with bucillamine. D-penicillamine, on the other hand, showed no beneficial effects on arthritis except for inhibiting new bone formation. Our findings suggest that bucillamine has beneficial effects on type II collagen induced arthritis in rats and that its mechanism of action is different from those of D-penicillamine.
Bucillamine: N-(2-mercapto-2-methyl-propanoyl)-L-cysteine has recently been suggested to be effective in the treatment of rheumatoid arthritis (RA). The molecular structure of this compound is similar to that of D-penicillamine, except that bucillamine has 2 free sulfhydryl groups in its structure whereas D-penicillamine has only one. The goal of our studies was to determine whether bucillamine exerted immunosuppressive effects in vitro.
The effect of bucillamine and its metabolites on mitogen induced proliferation and IL-2 production by human T cells was examined.
Bucillamine, and its metabolites SA 679, and SA 981 inhibited mitogen induced T cell responses. The inhibitory effect of bucillamine and SA 679, in which one sulfhydryl group is S-methylated, was markedly augmented in the presence of CuSO4, and the effect was completely prevented by the addition of catalase. The capacity of SA 981, the internal disulfide of bucillamine, to inhibit T lymphocyte responses was not dependent on the presence of CuSO4. SA 672, in which both sulfhydryl groups are S-methylated, did not inhibit T cell proliferation.
Our results suggest that bucillamine has 2 distinct inhibitory effects on T cell function. One is the ability to generate H2O2 in the presence of CuSO4 and is attributable to its free thiol groups. The other is related to a separate inhibitory mechanism, that is not dependent on CuSO4 or the reduced thiol groups. These 2 immunosuppressive effects may account for the potency of bucillamine in suppressing rheumatoid inflammation.
Bucillamine [N-(2-mercapto-2-methylpropionyl)-L-cysteine] (BUC) is a thiol compound that differs from D-penicillamine (DPC) in that it contains two free sulfhydryl groups. Clinical trials have demonstrated that its efficacy in rheumatoid arthritis is superior to that of DPC, but its mechanism of action remains unclear. We therefore examined the effects of BUC on the in vitro function of human B cells in comparison to those of DPC. IgM production was induced from highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus factors generated from mitogen-activated T cells (TF) or interleukin-2 (IL-2) or with immobilized anti-CD3-activated CD4+ T cells. BUC suppressed the production of IgM at concentrations of 0.3-100 micrograms/ml irrespective of the presence of CuSO4. Whereas BUC suppressed the production of IL-2 and interferon-gamma by immobilized anti-CD3-activated CD4+ T cells, its suppressive effects on the production of IgM in anti-CD3-stimulated cultures were not overcome by addition of TF or IL-2, indicating that the action of BUC involves direct inhibition of B cell function. BUC suppressed the initial stages of B cell activation, but not the maturation of previously activated B cells. In contrast to DPC, the suppressive activities of BUC did not require the presence of copper and were not overcome by the addition of monocytes or catalase. The effects of SA981, a metabolite of BUC with an intramolecular disulfide, on B cell function were more marked than those of BUC, whereas the effects of SA679, another metabolite of BUC with one of the two sulfhydryl bonds methylated, were similar to those of DPC. SA672, a metabolite of BUC with both of the two sulfhydryl bonds methylated, did not suppress B cell function. These results indicate that BUC as well as some of its metabolites inhibit cytokine production by T cells and also suppress the production of IgM at least in part by directly inhibiting B cells. These compounds exert immunosuppressive effects that are similar to those of DPC, but also unique inhibitory effects that depend upon the capacity of BUC to form an intramolecular disulfide between its two sulfhydryl groups.
In order to compare the clinical effect and the frequency of side effect of D-penicillamine and bucillamine, we conducted a randomized, controlled clinical trial. Twenty-two and 24 patients were allocated to each section of the study, respectively. Bucillamine was at least as effective ad D-penicillamine in terms of improvement in the swollen joint count, tenderness score, morning stiffness, modified health assessment questionnaire, and Westergren erythrocyte sedimentation rate (ESR), and more effective in terms of improvement in the tender joint count, grip strength, C-reactive protein (CRP), and rheumatoid factor (RF) titer. In all, 27% of the bucillamine group and 33% of the D-penicillamine group responded; the response rate did not differ significantly between the two groups. The frequency of side effects tended to be lower in the bucillamine group. In conclusion, bucillamine was as effective as D-penicillamine in the treatment of rheumatoid arthritis, and with the former the frequency of side effects tended to be lower.
SA96 (generic name, bucillamine) is a disease-modifying anti-rheumatoid arthritis (RA) drug with immunological effects. This compounds has two sulfhydryl groups in its molecule, and the differences and similarities between this drug and D-penicillamine, which is also a sulfhydryl group-containing anti-rheumatic drug, have frequently been discussed. To clarify the pharmacological differences between these two drugs, we examined the concentrations of the compounds and its metabolites in serum and synovial fluid, paying special attention to the metabolites of SA96 produced in vivo. SA96 was metabolized in a very short time to SA981 which is a disulfide compound formed by intramolecular binding of two sulfhydryl groups, and transferred to synovial fluid. In addition SA981 had significant suppressive effects on IL-6 and IL-8 production by synovial cells in vitro. These results demonstrate that SA96, which has two sulfhydryl groups, exhibits anti-rheumatic effects via a pharmacological action clearly different from that of D-penicillamine.
We investigated the effects of bucillamine and N-acetyl-L-cysteine (NAC) on cytokine production and CIA. Bucillamine and NAC inhibited NF-kappaB activation and tumour necrosis factor-alpha (TNF-alpha) mRNA expression in human monocytic leukaemia cell line THP-1, and cytokine production from monocyte cell lines at concentrations >10-3 M. They also inhibited cytokine production and CIA in mice at a dose of 500 mg/kg. These results suggest that NF-kappaB inhibitors such as bucillamine and NAC may inhibit cytokine-related diseases, including arthritis.
Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis and is constitutively expressed in the synovium of rheumatoid arthritis (RA). Over-expression of VEGF may play an important role in pathogenic vascularization and synovial hyperplasia of RA. In the present study, we examined whether disease-modifying anti-rheumatic drugs (DMARDs), including bucillamine (BUC), gold sodium thiomalate (GST), methotrexate (MTX) and salazosulfapiridine (SASP), act by inhibiting the production of VEGF by cultured synovial cells of patients with RA. Treatment of cultured synoviocytes with lipopolysaccharide (LPS) significantly increased VEGF production by cultured synovial cells. BUC significantly inhibited LPS-induced VEGF production, while GST tended to inhibit the production of VEGF. The inhibitory effects on VEGF production were dose-dependent. In contrast, MTX and SASP did not affect VEGF production. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that BUC also inhibited LPS-induced VEGF mRNA expression in RA synovial cells. The present study provides the first evidence that BUC inhibits VEGF production and the expression of its mRNA in synovial cells of RA patients. Our results indicate that the anti-rheumatic effects of BUC are mediated by suppression of angiogenesis and synovial proliferation in the RA synovium through the inhibition of VEGF production by synovial cells.
We investigated the effects of various sulfhydryl compounds on interleukin-1 (IL-1)-induced vascular endothelial growth factor (VEGF) production in human synovial stromal cells (HSSC). HSSC stimulated by IL-1beta (100 ng/ml) produced VEGF and interleukin-6 (IL-6) in vitro. Monosulfhydryl compounds, N-acetylcysteine, D-penicillamine, tiopronin and the bucillamine-like disulfhydryl compound, compound A scarcely affected VEGF or IL-6 production at concentrations of 10(-5) and 10(-4) M. However, the disulfhydryl compound, bucillamine inhibited VEGF production but not IL-6 production at concentrations of 10(-5) and 10(-4) M. These results suggest that bucillamine may be a selective inhibitor of IL-1-induced VEGF production in HSSC, and that inhibition of VEGF production may require not only SH groups but also a specific chemical structure.
Injury during reperfusion can partially offset the benefit of relief of ischemia in myocardial infarctions rapidly treated with thrombolytic drugs or angioplasty. We assessed whether bucillamine (N-[2-mercapto-2-methylpropionyl]-L-cysteine) is potentially useful to treat myocardial reperfusion injury. Bucillamine is a potent sulfhydryl donor not previously tested as a treatment of reperfusion injury. Cardiac myocytes were exposed to hydrogen peroxide or a xanthine/xanthine oxidase system resulting in injury-induced release of lactate dehydrogenase. Bucillamine (125-500 microM) prevented lactate dehydrogenase release in a concentration-dependent manner. Bucillamine, which has two donatable thiol groups, was twice as protective as N-2-mercaptopropionyl glycine, which contains a single donatable thiol group. Dogs were then exposed to 90 min of coronary artery occlusion and 48 h of reperfusion before sacrifice. Beginning at the onset of reperfusion, bucillamine, 11 or 22 mg/kg per hour, or vehicle (saline) was administered intravenously for 3 h. There was a dose-related response to bucillamine for infarct size, normalized for size of the region at risk and adjusted for collateral blood flow to the ischemic region. Infarct size was reduced by 41% in the group treated with bucillamine 22 mg/kg per hour, compared with the vehicle group. Bucillamine, probably through an antioxidant mechanism, reduced infarct size when administered during reperfusion.
We investigated the inhibitory effects of bucillamine on formation of laser-induced choroidal neovascularization (CNV) in a rat model.
Bucillamine administration (approximately 150 mg/kg/day) was started 1 week before photocoagulation and continued to the end of the study. Control groups received drinking water. Two weeks after photocoagulation, choroidal neovascularization development was evaluated using simultaneous fluorescein and indocyanine green angiography, and the maximal thickness of the lesions was measured histologically.
The incidence of CNV formation was 99.5 +/- 0.2% [mean +/- standard deviation (SD)] in control rats and 64.3 +/- 15.1% with bucillamine (P < 0.01). Histological study showed that the thickness of the CNV lesions was 23.4 +/- 6.5 microm (mean +/- SD) in the bucillamine-treated rats, which was significantly decreased compared to that in controls (60.8 +/- 9.2 microm) (P < 0.01).
Our results suggest that bucillamine may inhibit the development of laser-induced CNV in rats.
Vascular endothelial growth factor (VEGF) plays an important role in the neovascularization of ischaemic retinal diseases such as proliferative diabetic retinopathy. We determined that bucillamine, an anti-rheumatic drug, inhibits the VEGF production induced by hypoxia in bovine retinal microcapillary endothelial cells (BREC). To further clarify the inhibitory mechanism, we investigated the possible mechanism by which bucillamine exerts this inhibitory effect.
Bucillamine (100 μM) decreased the hypoxia-induced increase of VEGF mRNA by 54.5% (P<0.001). Bucillamine (100 μM) reduced the hypoxia-induced VEGF content in culture media by 29.0% (P<0.001), while monosulfydryl drugs, N-acetylcysteine and D-penicillamine, did not.
Bucillamine (100 μM) did not affect VEGF mRNA half-life (hypoxia, 4.3 h; hypoxia+bucillamine, 3.9 h; normoxia, 2.7 h; normoxia+bucillamine, 2.7 h).
Reporter gene studies revealed that bucillamine reduced transcriptional activity in the 5′-flanking region of the VEGF gene by 74.0%. Hypoxia stimulated binding activity of BREC nuclear protein to a hypoxia responsive element (HRE), which was decreased by bucillamine.
Bucillamine inhibited hypoxic-induction of HIF-1α mRNA by 73.1% (P<0.001). Bucillamine also inhibited spontaneous VEGF mRNA expression by 26.6%. Furthermore, it inhibited activity of VEGF promoter and decreased binding activity to Sp1 and HRE, but did not alter AP1 and AP2 activity in normoxia.
These data suggest that bucillamine inhibits hypoxic induction of VEGF through inhibition of HIF-1 induction and binding activity in BREC. Bucillamine also inhibits the spontaneous expression of VEGF mRNA by its effect on Sp1 and HRE binding.
British Journal of Pharmacology (2002) 137, 901–909. doi:10.1038/sj.bjp.0704929
B cells appear to have a central role in the immunopathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE); both autoantibody production and B-cell anomalies are characteristic of these diseases. With the recent availability of biologic agents that can deplete B cells or block their function in vivo, it has become possible to target B cells therapeutically. Evidence strongly suggests that novel B-cell targeting agents are effective. In addition, the mechanistic specificity of B-cell targeted approaches, combined with the ability to test them in large randomized controlled trials, will provide an unprecedented opportunity to study the precise roles of B cells in the immunopathogenesis of RA and SLE. The largest volume of information is available for rituximab, a chimeric monoclonal antibody that depletes B cells by binding to the CD20 cell-surface antigen. Information from multiple investigator-sponsored trials and from off-label use suggests efficacy of this antibody in RA, SLE, and other autoimmune syndromes. Randomized controlled trials have also provided solid evidence for the efficacy of rituximab in RA and are ongoing in SLE. Other therapeutic agents supported by controlled data include cytotoxic T-lymphocyte-associated protein 4 immunoglobulin and antibodies against the interleukin-6 receptor and the B-cell survival molecule BLyS. Additional agents and targets are in earlier stages of development. The concerns about infectious complications have so far not proven to be justified. We can reasonably expect important advances in the understanding and treatment of RA and SLE in the next 5-10 years, as B-cell targeting methods become more widespread and sophisticated.
Bucillamine has potential to attenuate or prevent damage during myocardial infarction, cardiac surgery and organ transplantation. Bucillamine, a cysteine derivative that contains two donatable thiol groups, is capable of replenishing the thiol group in glutathione, thereby reactivating this endogenous defense against oxidant injury. Bucillamine rapidly enters cells by the same mechanism that normally transports the amino acid cysteine. Bucillamine is a more potent thiol donor than other cysteine derivatives: approximately 16-fold more potent than N-acetylcysteine (Mucomyst(R)) in vivo. In addition bucillamine appears to have additional anti-inflammatory effects unrelated to its antioxidant effect. Oral bucillamine is used clinically in Asia for treatment of rheumatoid arthritis. There is a strong preclinical evidence that parenteral infusion of this agent is efficacious in acute settings characterized by inflammation and oxidative stress. In an investigator-blinded, rigorous intact dog model, consisting of 90 min of coronary artery occlusion and 48 h of reperfusion, bucillamine, given i.v. during the first 3 h of reperfusion, substantially reduced myocardial infarct size. Livers exposed to 24 h of cold ischemia were markedly protected by bucillamine in several transplantation models. In Phase I human studies in normal volunteers, bucillamine at doses up to 25 mg/kg/h i.v. for 3 h elicited no serious toxicity. On the basis of pharmacokinetic analyses of blood levels during these studies it was concluded that bucillamine, infused at i.v. doses > or =10 mg/kg/h for 3 h to humans could be expected to be therapeutically effective in myocardial infarction, organ transplantation and other acute inflammatory syndromes.
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