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ID PMID Title PublicationDate abstract
18166219 Insights into the pathology and treatment of spondyloarthritis: from the bench to the clin 2008 Oct OBJECTIVE: The spondyloarthritides are a set of chronic inflammatory diseases that consists of 5 interrelated subsets (ankylosing spondylitis [AS], psoriatic arthritis [PsA], reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy). The aim of this review was to evaluate the classification, genetic susceptibility, pathology, and response to treatment of spondyloarthritis (SpA). METHODS: Searches were conducted of the PubMed database for articles focusing on the classification, pathology, and treatment of SpA. RESULTS: The 5 subsets of SpA share many clinical, immunohistochemical, and genetic features, including the common presence of human leukocyte antigen-B27 and the absence of rheumatoid factor. Evidence suggests that the pathology of SpA is mediated by immune cells. In particular, tumor necrosis factor-alpha appears to be an important driver of inflammation and damage in SpA. A number of different SpA classification criteria have been developed, including the Modified New York Criteria for AS, the European Spondyloarthropathy Study Group criteria, the Amor criteria, as well as criteria for PsA, notably the Moll and Wright criteria and the Classification of Psoriatic Arthritis criteria. Suboptimal efficacy and adverse effects often limit the use of conventional pharmacologic treatments for SpA, including nonsteroidal antiinflammatory drugs and disease-modifying antirheumatic drugs, such as methotrexate and sulfasalazine. Recent evidence has demonstrated that targeted biologic response modifiers, such as TNF-alpha antagonists, are well tolerated and efficacious treatments for SpA. CONCLUSIONS: Significant advances have occurred in our understanding of the pathophysiology, diagnosis, and classification of the spondyloarthritides and effective treatments are available.
18727021 Topical delivery of methotrexate via skin pretreated with physical enhancement techniques: 2008 Sep BACKGROUND AND OBJECTIVE: The high hydrophilicity and molecular weight of methotrexate (MTX) make it difficult to deliver via the skin route for treating psoriasis or rheumatoid arthritis. The objective of this study was to enhance and optimize the skin permeation of MTX using two physical techniques: an erbium:yttrium-aluminum-garnet (Er:YAG) laser and electroporation. METHODS: In vitro skin permeation was performed using horizontal side-by-side diffusion cells. The animal model utilized nude mice. The skin where epidermal hyperproliferation was reproduced by repeated barrier abrogation was also used as a permeation barrier for MTX delivery. RESULTS: Application of the laser and electroporation significantly enhanced the permeation of MTX. The enhancing effect was more pronounced after applying the laser. Er:YAG laser pretreatment on the skin produced a 3- to 80-fold enhancement dependent upon the magnitude of the laser fluence. Using electroporation, treatment with 10 pulses resulted in a twofold increase in MTX flux. A combination of laser pretreatment and subsequent electroporation for 10 minutes resulted in a higher drug permeation than either technique alone. However, this synergistic effect was only observed when the lower laser fluence (1.4 J/cm(2)) was applied. Hyperproliferative skin generally showed a greater variability of MTX flux and lower permeation. CONCLUSION: The results shown in the present study encourage further investigation of laser- and electroporation-assisted topical drug delivery.
17263820 Sézary syndrome in a patient receiving infliximab for ankylosing spondylitis. 2007 Apr Infliximab, a tumour necrosis factor (TNF)-alpha antagonist, has shown striking efficacy in the treatment of chronic inflammatory rheumatological diseases such as rheumatoid arthritis and ankylosing spondylitis. However, long-term follow-up studies support that treatment with infliximab is associated with an increased risk of non-Hodgkin lymphoma. So far, few cases of cutaneous lymphoma have been reported in patients receiving TNF-alpha-blocking agents. We report a patient who developed Sézary syndrome 17 months after the onset of infliximab therapy for ankylosing spondylitis. Cutaneous lesions partially remitted following infliximab withdrawal and methotrexate treatment. Although the causal link between infliximab and the emergence of Sézary syndrome is uncertain, the present case raises the need for exhaustive long-term registries of malignancies, including primary cutaneous lymphomas, in patients receiving TNF-alpha-blocking agents.
17158115 Adult-onset Still's disease in a patient over 80 years old successfully treated with low-d 2007 Jan We report on an 83-year-old Japanese woman with adult-onset Still's disease (AOSD), with marked hypercytokinemia (serum levels of ferritin (Fer) and interleukin (IL)-18 were markedly high). On seeing older patients with fever of unknown origin (FUO), particularly Asians, AOSD should be considered. Reduced doses of oral prednisolone following intravenous methylprednisolone (mPSL) therapy caused a flare-up of AOSD and led to Pneumocystis carinii (jeroveci) pneumonia. Low-dose methotrexate (MTX) therapy was administered as a steroid-sparing agent with good response. Our case suggests that in very elderly people, as in younger patients, MTX is useful for controlling AOSD with marked hypercytokinemia, and avoiding corticosteroid-induced adverse effects.
19014870 Treatment with etanercept in six patients with chronic hepatitis C infection and systemic 2008 Dec OBJECTIVE: To describe the clinical and immunologic features of 6 patients with rheumatic disease and Hepatitis C Virus (HCV) chronic infection, treated with anti-TNF alpha drugs. PATIENTS AND METHODS: Six patients, with repeated positive serology for HCV infection, were affected by Rheumatoid arthritis (RA) (4 cases), Psoriatic Arthritis (PsA) and Polymyositis in one case each. They started anti-TNFalpha treatment (Etanercept), due to a previous failure of combination of different immunosuppressants (Methotrexate, Sulfasalazine, Cyclosporine, Hydroxychloroquine). RESULTS: Patients (3 female and 3 males) showed a mean age at disease onset of 50.6 years (SD 14.5) and a mean disease duration of 12.5 years (SD: 8.8). Etanercept (dosage of 50 mg weekly) was continued for a median period of 14 months. Patients affected by RA and PsA achieved a good clinical response, with a significant reduction of DAS28 during treatment (p: 0.0001). No patient received any specific therapy for HCV infection. Elevated HCV-RNA titres were recorded in 5 cases at start of Etanercept. No significant increase was observed during anti-TNF alpha treatment. No cases of hepatic failure were recorded. CONCLUSION: Anti-TNF alpha therapy showed to be effective, safe and well tolerated in the setting of HCV infection.
18678279 Cytotoxic and genotoxic effects of methotrexate in germ cells of male Swiss mice. 2008 Aug Methotrexate (MTX) is an anti-metabolite drug widely used in the treatment of neoplastic disorders, rheumatoid arthritis and psoriasis. Developed as an analogue of folic acid, it inhibits purine and pyrimidine synthesis that accounts for its therapeutic efficacy as well as for its toxicities. MTX has narrow therapeutic index and its toxicity has been reported in various organ systems including gastrointestinal, haematologic and central nervous system. The objective of the present study is to investigate the germ cell toxicity induced by MTX in male Swiss mice. MTX was administered intraperitoneally (ip) at the doses of 5, 10, 20 and 40 mg/kg to mice (20-25 g) weekly once (wk) for 5 and 10 weeks. The animals were sacrificed 1 week after receiving the last treatment of MTX. The germ cell toxicity was evaluated using testes weight (wt), sperm count, sperm head morphology, sperm comet assay, histology, TUNEL and halo assay in testis. MTX treatment significantly reduced the sperm count and increased the occurrence of sperm head abnormalities in a dose dependent manner. It induced the testicular toxicity as evident from the histology of testis. Sperm comet, TUNEL and halo assay in testis also revealed significant DNA damage after MTX treatment. On the basis of the present study, it can be concluded that MTX induced germ cell toxicity in mice.
17039308 Evaluation of Pneumocystis pneumonia infection risk factors in patients with connective ti 2006 We conducted a retrospective, clinical evaluation of connective tissue disease (CTD) patients who were tested for either sputum or bronchoalveolar lavage fluid Pneumocystis polymerase chain reaction (PC-PCR) and analyzed the risk factors that cause Pneumocystis pneumonia (PCP) susceptibility and fatality. PC-PCR was performed on 66 CTD patients who presented with symptoms, data, or radiological findings strongly suggesting respiratory infection. Patients with higher oral corticosteroid doses, use of oral methotrexate (MTX), bilateral lung findings, positive beta-D-glucan, and no prophylaxis use were more susceptible to PCP. They had significantly low immunoglobulin G and significantly high beta-D-glucan and lactate dehydrogenase. Survivors and nonsurvivors of PCP were also evaluated. Poor prognoses were observed with older age, elevated beta-D-glucan, rheumatoid arthritis (RA) patients using MTX, hypoxemia, bilateral lung findings, and mechanical ventilation use. Nonsurvivors had significantly lower lymphocytes, oxygen saturation, and significantly higher beta-D-glucan. In RA, poor prognoses were seen with those taking MTX. Disease duration, underlying pulmonary complications, and oral corticosteroid doses did not lead to poor prognoses in RA. Because PCP in CTD leads to abrupt onset of symptoms with poor survival rates, early diagnosis and initiation of treatment are critical, and it is essential for clinicians to recognize risk factors that predispose patients to PCP and its mortality.
16447232 Acquired resistance to chloroquine in human CEM T cells is mediated by multidrug resistanc 2006 Feb OBJECTIVE: To explore the onset and molecular mechanism of resistance to the antimalarial disease-modifying antirheumatic drug (DMARD) chloroquine (CQ) in human CEM T cells. METHODS: Human CEM cells were used as an in vitro model system to study the development of CQ resistance by growing cells in stepwise increasing concentrations of CQ. RESULTS: Over a period of 6 months, CEM cell lines developed 4-5-fold resistance to CQ. CQ resistance was associated with the specific overexpression of multidrug resistance-associated protein 1 (MRP-1), an ATP-driven drug efflux pump. This was illustrated by 1) overexpression of MRP-1 by Western blotting and 2) the complete reversal of CQ resistance by the MRP-1 transport inhibitors MK571 and probenecid. Importantly, CQ-resistant CEM cells retained full sensitivity to other DMARDs, including methotrexate, leflunomide, cyclosporin A, and sulfasalazine, but exhibited a high level of cross-resistance (>1,000-fold) to the glucocorticoid dexamethasone. The mechanistic basis for the latter was associated with aberrant signaling via the cAMP-protein kinase A pathway, since the cAMP-inducing agent forskolin reversed dexamethasone resistance. Finally, CQ-resistant CEM cells displayed a markedly reduced capacity to release proinflammatory cytokines (tumor necrosis factor alpha) and chemokines (interleukin-8). CONCLUSION: Induction of overexpression of the multidrug resistance efflux transporter MRP-1 can emerge after long-term exposure to CQ and results in CQ resistance and collateral resistance to dexamethasone. These findings warrant further detailed investigations into the possible role of MRP-1 and other members of the superfamily of drug efflux pumps in diminishing the efficacy of DMARDs in rheumatoid arthritis treatment.
18829735 Early-onset pancytopenia and skin ulcer following low-dose methotrexate therapy. 2008 Jul Pancytopenia is a rare but serious adverse effect of low-dose methotrexate (MTX) sodium therapy, and this case report describes a very early-onset of pancytopenia and cutaneous lesions after three days of ingestion. A 64-year-old man was presented to Emergency Department with weakness, fever, poor appetite, nausea, and vomiting after he had had accidentally ingested MTX tablets (2.5 mg) twice a day for the last three days. On initial examination, several painful lesions in his oral mucosa and a cutaneous ulceration on his right foot were also observed. He had severe pancytopenia, poor kidney functions, and abnormal coagulation parameters. The blood level of MTX was found to be within therapeutic range. He was treated with leucovorine, intravenous antibiotics, and appropriate blood transfusions; he was discharged from hospital without any sequela. Pancytopenia associated with low-dose (cumulative dose of 15 mg in 3 days) MTX therapy had not been reported previously. The Naranjo probability scale showed pancytopenia and skin ulcer associated with low-dose MTX therapy as probable adverse reactions. Risk factors for pancytopenia such as renal insufficiency, hypoalbuminemia, low folate levels, concomitant infections, concomitant use of drugs, and folate supplementation were not identified in our patient. Although pancytopenia associated with low-dose MTX therapy is not expected as early as 3 days after initiation of the therapy, physicians should also be aware of this life threatening adverse effect during the very first days of MTX therapy for rheumatoid arthritis patients.
17517083 Audit of pneumocystis pneumonia in patients seen by the Christchurch Hospital rheumatology 2007 Oct AIM: The aim of the study was to review all cases of Pneumocystis carinii pneumonia (PCP) in patients seen by the Christchurch Hospital Rheumatology service over a 5-year period and to determine the annual incidence of PCP. METHODS: The Canterbury Health Laboratory database was searched for rheumatology patients testing positive for PCP from 31 December 2000 to 31 December 2005. The rheumatology database was then searched to identify patients receiving the same immunosuppressant medication as those who developed PCP to determine the annual incidence of PCP in this group. RESULTS: Four rheumatology patients were diagnosed with PCP during the 5-year period. Two were receiving oral methotrexate (MTX) for rheumatoid arthritis and two were receiving cyclophosphamide (CYC), one each for Wegener's granulomatosis and dermatomyositis. None of the four cases was receiving PCP chemoprophylaxis. Five hundred and forty-seven patients commenced MTX over the same 5-year period and 47 commenced CYC. Only 14 of 47 (29.7%) CYC-treated patients received PCP prophylaxis. The annual incidence of PCP was 0.17% (95% confidence interval (CI) 0.02-0.63) and 5.33% (95%CI 0.65-19.24) in patients prescribed MTX and CYC, respectively. For the 33 patients receiving CYC without concomitant PCP prophylaxis the annual incidence was 9.50% (95%CI 1.15-34.33). CONCLUSION: In our study the annual incidence of PCP in patients taking MTX was low and would not support the use of routine PCP chemoprophylaxis. In patients receiving CYC without concomitant PCP chemoprophylaxis the annual incidence of PCP was higher although the number of cases was small. Given the high morbidity and mortality in this group, PCP chemoprophylaxis should be considered.
18535937 Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders 2008 Jun Genmab A/S and licensee GlaxoSmithKline plc are developing ofatumumab, an anti-CD20 human mAb, for the potential intravenous treatment of non-Hodgkin's lymphoma and autoimmune diseases, such as rheumatoid arthritis (RA) and multiple sclerosis (MS). Phase I and II clinical trials have been completed in patients with chronic lymphocytic leukemia (CLL), rituximab-refractory follicular lymphoma (FL) and RA. At the time of publication ofatumumab was undergoing a phase II clinical trial in patients with diffuse large B-cell lymphoma and phase III clinical trials in patients with B-cell CLL (B-CLL) in which fludarabine and alemtuzumab treatments have failed and in patients with rituximab-refractory FL. Ofatumumab was also undergoing phase II clinical trials as a combination therapy for previously untreated patients with FL in combination with cyclophosphamide, adriamycin, vincristine, and prednisone and in combination with fludarabine and cyclophosphamide for the treatment of B-CLL. In addition, two phase III clinical trials to assess patients who have an inadequate response to methotrexate and TNFalpha therapy were ongoing for patients with RA, and a phase II clinical trial to investigate the effects of repeated doses of ofatumumab was recruiting patients with RA from a previous trial on ofatumumab. A phase I/II clinical trial of ofatumumab in relapsing-remitting MS was expected to commence in 2008.
18461290 Spontaneous remission of "methotrexate-associated lymphoproliferative disorders" after dis 2009 There are a number of intriguing reports of lymphoproliferative disorders (LPDs) diagnosed during immunosuppressive treatment for underlying autoimmune disease, and spontaneously abated shortly after treatment discontinuation. Such LPDs, completely or partially regressing, occur in the clinical setting of "Methotrexate (MTX)-associated LPDs", recognized by the World Health Organization (WHO) among the "Immunodeficiency-associated LPDs". We identified 26 literature patients achieving spontaneous complete remission (CR) of their LPD, and eight others showing partial remission (PR). Most of them were affected by rheumatoid arthritis, received low-dose and long-term pulsed MTX alone or combined with other immunosuppressants, and developed a lymphoma. By reviewing the patients achieving CR, the following can be drawn: the absence of a unique type of LPD, the occurrence of an increased incidence of diffuse large B cell lymphoma as well as of frequent extranodal involvement, and EBV-infection. Further, CR mostly occurred within 4 weeks after discontinuation of immunosuppressant, and appeared to be persistent overtime. Conversely in the patients experiencing PR, the interval between discontinuation of immunosuppressive treatment and clinical response was mostly reported as longer than 4 weeks; moreover, in many cases the persistence of LPD or its progression induced to start cytotoxic therapy. Increased awareness is needed on the possible occurrence of LPD spontaneous remission following immunosuppressant discontinuation, after that it is therefore advisable to have a careful monitoring of the patient for some weeks, before starting cytotoxic therapy.
16927044 Methotrexate, azathioprine, cyclosporine, and risk of fracture. 2006 Aug We studied the fracture risk associated with use of methotrexate, azathioprine, and cyclosporine. The study was designed as a case-control study. All patients with a fracture (n = 124,655) in the year 2000 in Denmark served as cases. Information on fractures and confounders was retrieved from the National Hospital Discharge Register and a number of other national registers. For each case, three age- and gender-matched controls were randomly drawn from the general population (n = 373,962). Exposure was use of the drugs and a number of covariates including other immunosuppressive drugs, corticosteroids, any cancer, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, liver and kidney disease, prior fracture, and alcoholism. Azathioprine was associated with an increase in overall fracture risk, but besides this, none of the drugs was significantly associated with overall fracture risk or risk of hip, spine, or forearm fracture. Liver [odds ratio (OR) = 1.55, 95% confidence interval (CI) 1.42-1.69] and kidney (OR = 1.26, 95% CI 1.16-1.37) diseases were significantly associated with increased risk of fractures. Azathioprine was associated with an increase in overall fracture risk but not in the risk of spine, hip, or forearm fractures. Methotrexate and cyclosporine were not associated with fracture risk. It thus seems that the underlying disease for which the treatment is administered may be responsible for much of the increase in fracture risk rather than the drugs used to treat the disorder in question.
16368293 The nonspecific anti-inflammatory therapy with methotrexate for patients with chronic hear 2006 Jan BACKGROUND: Inflammatory mediators play an important role in the pathogenesis of chronic heart failure (CHF). Methotrexate (MTX) is used in the treatment of inflammatory-mediated diseases (eg, rheumatoid arthritis) because it modulates the expression of numerous inflammatory cytokines. However, no studies have assessed the effects of MTX on plasma levels of inflammatory mediators in patients with CHF. METHODS: In a prospective, randomized, placebo-controlled, single-blind study, 71 patients receiving conventional treatment were randomly allocated to either MTX group (7.5 mg once a week, n = 35) or placebo group (n = 36) with a follow-up of 12 weeks. The effects of MTX on plasma cytokine expression, left ventricular ejection fraction, left ventricular end-diastolic dimension, New York Heart Association (NYHA) functional class, 6-minute walk test distance, and quality of life (QOL) were determined in patients with CHF. RESULTS: Sixty-two patients completed the study. The circulating levels of inflammatory mediators in patients with CHF were markedly elevated compared with healthy controls (P < or = .002). Methotrexate (n = 30) reduced plasma levels of tumor necrosis factor alpha (-15.6%, P < .05), interleukin 6 (-21.8%, P < .01), monocyte chemoattractant protein-1 (-22.6%, P < .01), soluble intercellular adhesion molecule-1 (-19.2%, P < .05), and C-reactive protein (-27.2%, P < .01) compared with baseline. Furthermore, interleukin 10 (15.8 %, P < .05) and soluble IL-1 receptor antagonist (36.1%, P < .01) expression was increased, whereas improvements in NYHA classification, 6-minute walk test distance, and QOL were found compared with baseline. Monocyte chemoattractant protein-1 expression was lower and soluble IL-1 receptor antagonist expression higher in the MTX than placebo group (n = 32). Furthermore, the left ventricular ejection fraction, left ventricular end-diastolic dimension, and incidence of main adverse cardiac events between the 2 groups were similar. CONCLUSION: These results suggest that the addition of MTX to conventional therapy for CHF has significant anti-inflammatory effects and improves NYHA functional class, 6-minute walk test distance, and QOL.
16533508 Effect of glutamate receptor antagonists and antirheumatic drugs on proliferation of synov 2006 Mar 27 One of the most striking features of inflammatory arthritis is the hyperplasia of synovial fibroblasts. It is not known whether the massive synovial hyperplasia characteristic of rheumatoid arthritis is due to the proliferation of synovial fibroblasts or to defective apoptosis. It has been found that glutamate receptor antagonists inhibit proliferation of different human tumour cells and the anticancer potential of glutamate receptor antagonists was suggested. Here, we investigated the effect of glutamate receptor antagonists and selected antirheumatic drugs on proliferation of synoviocytes in vitro. Experiments were conducted on rabbit synoviocytes cell line HIG-82 obtained from American Type Culture Collection (Menassas, VA, USA). Cell proliferation was assessed by means of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. Glutamate receptor antagonists, 1-(4-aminophenyl)-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-one (CFM-2), riluzole, memantine, 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466), dizocilpine, ketamine and 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.014, 0.017, 0.065, 0.102, 0.15, 0.435 and 1.16, respectively. Antirheumatic drugs, celecoxib, diclofenac, nimesulide, sulfasalazine, naproxen and methotrexate, inhibited proliferation of synoviocytes with the following IC50 values (in mM): 0.0043, 0.034, 0.044, 0.096, 0.385 and 1.123, respectively. Thus, the antiproliferative potential of glutamate receptor antagonists is comparable to that of antirheumatic drugs.
17703372 Parotid gland involvement, the presenting sign of high grade non-Hodgkin lymphoma in two p 2007 Oct Increased risk of haematological malignancies has been described in Gaucher disease patients; however, high-grade lymphoma has been rarely observed. We report two patients with Gaucher disease and sicca syndrome diagnosed with aggressive lymphoma involving the parotid gland. A 29-year-old woman with Gaucher disease developed tumour of the left parotid gland. She reported chronic arthralgias, xerostomia and xerophthalmia. Parotid gland biopsy disclosed diffuse large B-cell lymphoma. No lymphadenopathy was found. Bone biopsy revealed focal lymphomatous infiltration consistent with stage IV disease. MACOP-B chemotherapy regimen (cyclophosphamide, adriamycin, methotrexate, bleomycin, vincristine, prednisone) resulted in complete remission for 15 years. A 76-year-old patient with Gaucher disease suffered from dry-mouth feeling. He developed a left parotid gland tumour. CT scan disclosed diffuse lymphadenopathy, pleural effusion and multiple lung nodules. A cervical lymph node biopsy revealed mantle cell lymphoma. Fine-needle aspiration of the parotid gland showed lymphoma cells. Immunochemotherapy with fludarabine, cyclophosphamide and rituximab resulted in complete remission. Accumulation of the glucocerebroside in Gaucher disease activates macrophages, inducing release of pro-inflammatory cytokines which may be involved in the pathogenesis of second malignancy. Patients with Gaucher disease bear an increased risk of haematological malignancies; however, aggressive lymphoma has been described only occasionally. In both our patients the presenting sign of lymphoma was tumour of the parotid gland. The patients suffered from sicca syndrome, which increases risk for developing lymphoma. The underlying Gaucher disease and sicca syndrome might be implicated as immunological triggers for lymphoma occurrence and its propensity for the parotid gland in these patients.
18591874 Design and development of hydroxypropyl methycellulose (HPMC) based polymeric films of met 2008 Jul The present investigation was aimed to evaluate the possibility of using different concentrations and polymeric grades of hydroxypropyl methylcellulose (K4M, K15M and K100M) for transdermal delivery of methotrexate, an immunosuppressant drug for rheumatoid arthritis. The matrix films were evaluated for their physicochemical characterization followed by in vitro and in vivo evaluation. Selected formulations were subjected for their in vivo studies on healthy rabbits following balanced incomplete block design. The relevance of difference in the in vitro dissolution rate profile and pharmacokinetic parameters (C(max), t(max), AUC((s)), t(1/2), K(el), and MRT) were evaluated statistically. The thickness and weight of the patch increased with the increase in polymeric grade and content. Fourier transform infrared spectroscopy and differential scanning calorimetry results confirm that there is no interaction between drug and polymer used. X-ray diffraction study reveals an amorphous state of drug in the matrix films. The in vitro drug release followed Higuchi kinetics (r=0.972-997; p<0.001) as its coefficient of correlation values predominates over zero order and first order release kinetics. In vitro dissolution profiles and pharmacokinetic parameters showed a significant difference between test products (p<0.01), but not within test products. A quantitatively good correlation was found between per cent of drug absorbed from the transdermal patches and AUC((s)). A significant in vitro/in vivo correlation was observed when per cent drug released was correlated with serum drug concentration. Out of the various formulations made, the selected formulations are better in their in vitro dissolution and pharmacokinetic characteristics and thus hold potential for transdermal delivery.
17542999 Has the use of disease-modifying anti-rheumatic drugs changed as a consequence of controll 2007 Sep BACKGROUND: A prerequisite for access to biological agents for the treatment of rheumatoid arthritis under Australia's Pharmaceutical Benefits Scheme (PBS) is evidence of an adequate trial of conventional disease-modifying anti-rheumatic drugs (DMARDs). The aim of this study was to examine whether there were changes in prescribing DMARDs since the introduction of the PBS criteria for access to biologicals in August 2003. METHODS: A retrospective study was undertaken of the national use of DMARDs in the period before and after the introduction of biologicals under the PBS. Dispensing data were analysed for changes in patterns of DMARD prescription rates (2000-2005). RESULTS: There were 2 887 746 prescriptions for DMARDs between August 2000 and June 2005. PBS prescriptions accounted for 95% of these. Government expenditure for the DMARDs was $A156m. Trends in the use of DMARDs remained relatively steady over the study period without a significant change around the time the PBS criteria for biologicals were introduced. Use of hydroxychloroquine and leflunomide increased steadily, use of methotrexate and sulfasalazine was stable and use of gold preparations and penicillamine was considerably lower during this 5-year period. CONCLUSION: Introduction of PBS criteria for access to biologicals did not alter the trends in use of DMARDs based on national dispensing data. This study emphasized the value that would accrue from availability of more comprehensive, de-identified, individual patient data that would enable more detailed examination of the use of medicines. These data are available, but cannot be easily accessed. It is time to make the data available for approved, ethical research in the interests of better outcomes from medicines supplied under PBS.
17632266 Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. 2007 Jul Tumor necrosis factor (TNF)-targeted therapies are increasingly used for a rapidly expanding number of rheumatic and autoimmune diseases. With this use and longer follow-up periods of treatment, there are a growing number of reports of the development of autoimmune processes related to anti-TNF agents. We have analyzed the clinical characteristics, outcomes, and patterns of association with the different anti-TNF agents used in all reports of autoimmune diseases developing after TNF-targeted therapy found through a MEDLINE search of articles published between January 1990 and December 2006. We identified 233 cases of autoimmune diseases (vasculitis in 113, lupus in 92, interstitial lung diseases in 24, and other diseases in 4) secondary to TNF-targeted therapies in 226 patients. The anti-TNF agents were administered for rheumatoid arthritis (RA) in 187 (83%) patients, Crohn disease in 17, ankylosing spondylitis in 7, psoriatic arthritis in 6, juvenile RA in 5, and other diseases in 3. The anti-TNF agents administered were infliximab in 105 patients, etanercept in 96, adalimumab in 21, and other anti-TNF agents in 3. We found 92 reported cases of lupus following anti-TNF therapy (infliximab in 40 cases, etanercept in 37, and adalimumab in 15). Nearly half the cases fulfilled 4 or more classification criteria for systemic lupus erythematosus (SLE), which fell to one-third after discarding preexisting lupus-like features. One hundred thirteen patients developed vasculitis after receiving anti-TNF agents (etanercept in 59 cases, infliximab in 47, adalimumab in 5, and other agents in 2). Leukocytoclastic vasculitis was the most frequent type of vasculitis, and purpura was the most frequent cutaneous lesion. A significant finding was that one-quarter of patients with vasculitis related to anti-TNF agents had extracutaneous involvement. Twenty-four cases of interstitial lung disease associated with the use of anti-TNF agents were reported. In these patients, 2 specific characteristics should be highlighted: the poor prognosis in spite of cessation of anti-TNF therapy, and the possible adjuvant role of concomitant methotrexate. In conclusion, the use of anti-TNF agents has been associated with an increasing number of cases of autoimmune diseases, principally cutaneous vasculitis, lupus-like syndrome, SLE, and interstitial lung disease.
17400583 The contribution of methotrexate exposure and host factors on transcriptional variance in 2007 Jun Long-term administration of methotrexate (MTX) for management of chronic inflammatory diseases is associated with risk of liver damage. In this study, we examined the transcriptional profiles of livers from patients treated with MTX. The possibility that expression signatures correlate with grade of fibrosis or underlying rheumatic disease was evaluated. Twenty-seven patients taking MTX were accrued for this study. Ten non-MTX-exposed normal liver specimens were used as controls. Global mRNA expression was assayed using oligonucleotide arrays. A total of 205 genes were significantly altered in MTX-exposed livers. Six of these genes were validated by qPCR. Two genes, CLN8 and ANKH that map to chromosomal locations previously associated with rheumatoid arthritis, were found to be elevated in MTX-exposed samples. Subsequent pathway analysis indicates that MTX exposure is associated with the following key alterations: (1) upregulation of lipid biosynthetic genes, consistent with MTX-induced steatosis, (2) downregulation of proinflammatory chemokines, consistent with the anti-inflammatory effects of MTX, and (3) elevation of complement pathway gene expression. Complement 5, shown earlier to be correlated with liver fibrosis in mice, was found to be elevated (twofold) in MTX-exposed livers. In conclusion, we have found the expression of a number of genes associated with rheumatic disease and/or MTX exposure to be significantly different. Differences in complement expression provide the rationale for future correlative studies between MTX-induced liver fibrosis and C5 alleles in order to identify patients with increased risk for fibrosis.