TRIM46 contributes to high glucose-induced ferroptosis and cell growth inhibition in human retinal capillary endothelial cells by facilitating GPX4 ubiquitination.

PURPOSE: Increased permeability of retinal capillary endothelial cells is a key feature in the progression of diabetic retinopathy (DR). Precisely why and how diabetes causes dysfunction in retinal capillary endothelial cells is not well understood, making it challenging to explore more advanced therapeutics. METHODS: Cell proliferation was assessed by the Cell Counting Kit-8 assay. Ferroptosis was evaluated by measuring lipid reactive oxygen species levels by flow cytometry and determining malondialdehyde, superoxide dismutase, and glutathione peroxidase levels through biochemical assays. Western blot analysis and quantitative PCR were respectively used to check the expression of proteins and RNAs. Co-immunoprecipitation assays were used to confirm the interaction between TRIM46 and GPX4. RESULTS: High glucose (HG, 25 mM glucose) significantly suppressed cell growth, which could be reversed by the ferroptosis inhibitor, ferrostatin-1. HG treatment time-dependently induced ferroptosis in human retinal capillary endothelial cells (HRCECs) and induced TRIM46 expression. Lentiviral-mediated overexpression of TRIM46 decreased cell resistance against HG-induced ferroptosis, whereas knockdown showed the opposite effect. Administration of RSL3, a ferroptosis agonist, was able to reverse the protective effects of TRIM46 silencing. TRIM46 interacted with GPX4, an important enzyme that suppresses ferroptosis, and promoted GPX4 ubiquitination. Furthermore, lentiviral-mediated overexpression ofGPX4 ameliorated the effects of TRIM46 overexpression and conferred protection to cells against HG-induced ferroptosis. CONCLUSION: TRIM46 and GPX4 form a regulatory pathway that controls HG-induced ferroptosis of HRCECs. Inhibiting this pathway or sustaining the expression of GPX4 enables cells to resist damage caused by HG. We provide new mechanistic insight into the pathology of DR and identified TRIM46 and GPX4 as two molecular targets for the development of effective drugs for DR treatment.

Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects.

Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.

Actinomycin-D and dimethylamino-parthenolide synergism in treating human pancreatic cancer cells.

Preclinical Research & Development Pancreatic cancer is the third leading cause of death in the US with a poor 5-year survival rate of 8.5%. A novel anti-cancer drug, dimethylamino parthenolide (DMAPT), is the water-soluble analog of the natural sesquiterpene lactone, parthenolide. The putative modes of action of DMAPT are inhibition of the Nuclear chain factor kappa-light-chain enhancer of activated B cells (NFκB) pathway and depletion of glutathione levels; the latter causing cancer cells to be more susceptible to oxidative stress-induced cell death. Actinomycin-D (ActD) is a polypeptide antibiotic that binds to DNA, and inhibits RNA and protein synthesis by inhibiting RNA polymerase II. A phase 2 clinical trial indicated that ActD could be a potent drug against pancreatic cancer; however, it was not a favored drug due to toxicity issues. New drug entities and methods of drug delivery, used alone or in combination, are needed to treat pancreatic cancer more effectively. Thus, it was postulated that combining DMAPT and ActD would result in synergistic inhibition of Panc-1 pancreatic cancer cell growth because DMAPT's inhibition of NFκB would enhance induction of apoptosis by ActD, via phosphorylation of c-Jun, by minimizing NFκB inhibition of c-Jun phosphorylation. Combining these two drugs induced a higher level of cell death than each drug alone. A fixed drug ratio of DMAPT: ActD (1,200:1) was used. Data from metabolic (MTT) and colony formation assays were analyzed for synergism with CompuSyn software, which utilizes the Chou-Talalay equation. The analyses indicated synergism and moderate synergism at combination concentrations of DMAPT/ActD of 12/0.01 and 18/0.015 µM, respectively.

Mitomycin C in revision endoscopic dacryocystorhinostomy: a prospective randomized study.

BACKGROUND: Endoscopic dacryocystorhinostomy (EN-DCR) is an effective and safe procedure when treating saccal and postsaccal nasolacrimal duct obstruction. However, sometimes scarring of the rhinostomy site caused by fibrosis may occur, particularly in revision operations. The application of intraoperative mitomycin C (MMC), an antiproliferative agent, has been introduced as one possible technique to improve the outcome. We conducted a prospective, randomized study to evaluate if the use of MMC improves the success in endonasal revision DCR procedure. METHODS: Thirty revision EN-DCR procedures were performed during 2004-2010. The patients were randomized into two study groups, according to whether the intraoperative MMC was used or not. The technique of EN-DCR procedure in both groups was the same, but in the MMC group, at the end of the procedure a piece of tampon soaked in MMC (0.4 mg/mL) was placed into the rhinostoma for 5 minutes. No silicone stents were inserted. The surgical outcome at the 6-month follow-up visit was considered successful if the lacrimal sac irrigation succeeded and if the patients' symptoms were relieved. RESULTS: The success rate after revision EN-DCR with MMC was 93% and without MMC was 60%. The overall success rate was 77%. The difference between the two groups was not statistically significant (p = 0.08). The relief of the symptoms between groups in both the Nasolacrimal Duct Obstruction Symptom Score and ocular symptoms was statistically significant (p = 0.007 and p = 0.02, respectively). CONCLUSION: The results of our study indicate that the application of intraoperative mitomycin C may improve the outcome in revision EN-DCR.

IFN-γ promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation.

Duchenne muscular dystrophy is a degenerative disorder that leads to death by the third decade of life. Previous investigations have shown that macrophages that invade dystrophic muscle are a heterogeneous population consisting of M1 and M2 macrophages that promote injury and repair, respectively. In the present investigation, we tested whether IFN-γ worsens the severity of mdx dystrophy by activating macrophages to a cytolytic M1 phenotype and by suppressing the activation of proregenerative macrophages to an M2 phenotype. IFN-γ is a strong inducer of the M1 phenotype and is elevated in mdx dystrophy. Contrary to our expectations, null mutation of IFN-γ caused no reduction of cytotoxicity of macrophages isolated from mdx muscle and did not reduce muscle fiber damage in vivo or improve gross motor function of mdx mice at the early, acute peak of pathology. In contrast, ablation of IFN-γ reduced muscle damage in vivo during the regenerative stage of the disease and increased activation of the M2 phenotype and improved motor function of mdx mice at that later stage of the disease. IFN-γ also inhibited muscle cell proliferation and differentiation in vitro, and IFN-γ mutation increased MyoD expression in mdx muscle in vivo, showing that IFN-γ can have direct effects on muscle cells that could impair repair. Taken together, the findings show that suppression of IFN-γ signaling in muscular dystrophy reduces muscle damage and improves motor performance by promoting the M2 macrophage phenotype and by direct actions on muscle cells.

A profile of NSAID-targeted arachidonic acid metabolisms in human embryonic stem cells (hESCs): implication of the negative effects of NSAIDs on heart tissue regeneration.

INTRODUCTION: An emerging technology using human embryonic stem cells (hESCs) to regenerate infarcted heart tissue has been underdeveloped. However, because non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, are taken during the infarction, it becomes critical to know whether the NSAIDs have negative impacts on heart tissue regeneration when using hESCs. METHODS: Mass spectrometry (LC/MS/MS) and high performance liquid chromatography (HPLC) analyses were used to analyze the functional presence of the elaborate prostanoids' biosynthesis and signaling systems in hESCs. The detected endogenous arachidonic acid (AA) released in the hESC membranes reflects the activity of phospholipase which directly controls the biosyntheses of the prostanoids. RESULTS: The complete inhibition of the endogenous prostaglandin E(2) (PGE(2)) biosynthesis by the cyclooxygenase-2 (COX-2) inhibitor, NS398, confirmed that the major prostanoids synthesized in the hESCs are mediated by the COX-2 enzyme. We also found that PGE(2) and the prostacyclin (PGI(2)) metabolite, 6-keto-PGF(1α), are present in the undifferentiated hESCs. CONCLUSION: This indicated different cyclooxygenase (COX)-downstream synthases and metabolizing enzymes are involved in the AA products' signaling through the COX-1 and COX-2 pathways. The presence of many enzymes' and receptors' [(COX-1, COX-2, microsomal prostaglandin E synthase (mPGES), cytosolic prostaglandin E synthase (cPGES), prostaglandin I synthase (PGIS), the PGE(2) subtype receptors (EP(1), EP(2), and EP(4)) and the prostacyclin receptor (IP)] involvement in the prostanoid biosynthesis and activity was confirmed by western blot. The studies implied the negative effects of NSAIDs, such as aspirin and COX-2 inhibitors, which suppress prostanoid production during tissue regeneration for infarcted heart when using hESCs.

Induction of TGF-beta 1, not regulatory T cells, impairs antiviral immunity in the lung following bone marrow transplant.

Patients receiving hematopoietic stem cell transplantation or bone marrow transplantation (BMT) as therapy for various malignancies or autoimmune diseases have an increased risk for infectious complications posttransplant, especially in the lung. We have used BMT in mice and murine gammaherpesvirus, gammaHV-68, to study the efficacy of adaptive immune responses post-BMT. Five weeks posttransplant, mice have fully reconstituted their hematopoietic lineages in both the lung and periphery. When challenged with virus, however, BMT mice have a reduced ability to clear lytic virus from the lung. Defective viral control in BMT mice is not related to impaired leukocyte recruitment or defective APC function. Rather, BMT mice are characterized by defective CD4 cell proliferation, skewing of effector CD4 T cells from a Th1 to a Th17 phenotype, and an immunosuppressive lung environment at the time of infection that includes overexpression of TGF-beta1 and PGE(2) and increased numbers of regulatory T cells. Neither indomethacin treatment to block PG synthesis nor anti-CD25 depletion of regulatory T cells improved antiviral host defense post-BMT. Transplanting mice with transgenic bone marrow expressing a dominant-negative TGF-betaRII under the permissive CD4 promoter created mice in which effector CD4 and CD8 cells were unresponsive to TGF-beta1. Mice with TGF-beta1-nonresponsive effector T cells had restored antiviral immunity and improved Th1 responses post-BMT. Thus, our results indicate that overexpression of TGF-beta1 following myeloablative conditioning post-BMT results in impaired effector T cell responses to viral infection.

A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI), in patients with advanced solid tumours.

PURPOSE: The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery. METHODS: Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design. RESULTS: Thirty-seven patients received ZK 304709 from 15 to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria. CONCLUSIONS: There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.

[Proteinuria and renal transplantation]. / Importance du suivi de la protéinurie chez le transplanté

The occurrence of proteinuria in transplant patients is a marker of poor prognosis. The augmentation of proteinuria is associated with an increased risk of patient death and graft loss. Even a low-level urinary protein excretion (0.5 g/d) has a highly significant negative impact on graft survival whether it is observed 1 or 3 months after transplantation. Urinary albumin excretion rate has also a major effect on risks of graft loss and death with functional kidney, macro-albuminuria increasing the risks of respectively 16.4 and 4.12 times comparatively to micro-albuminuria, which itself multiplies the risks by 14.2 and 5.5 respectively, compared to normo-albuminuria. In terms of factors causing proteinuria apparition, the role of proliferation signal inhibitors has been recently observed. Sirolimus, especially at high dose, in particular can induce the occurrence of proteinuria, which is reversible with treatment discontinuation, but only with a partial recovery of the renal function. Proteinuria may be explained by a direct glomerular impact of sirolimus on several podocyte markers.

Inhibition of GSK-3 beta activity attenuates proliferation of human colon cancer cells in rodents.

The authors' recent discovery that glycogen synthase kinase-3beta (GSK-3beta) participates in colon cancer cells' survival and proliferation prompted us to investigate whether GSK-3beta inhibition alters proliferation of colon cancer cells in vivo. Groups of four or five athymic mice (Balb/c, nu/nu) with subcutaneous xenografts of SW480 human colon cancer cells were treated with dimethyl sulfoxide (DMSO) or different doses (1, 2 and 5 mg/kg body weight) of either small-molecule GSK-3beta inhibitor (SB-216763 and AR-A014418) by intraperitoneal injection three times per week for 5 weeks. Compared with DMSO (a diluent of the GSK-3beta inhibitors) as a control, either GSK-3beta inhibitor significantly inhibited proliferation of cancer cell xenografts in the rodents in a dose-dependent manner. Histochemical and immunohistochemical analysis of tumor xenografts demonstrated a significant, dose-dependent decrease in fractions of proliferating cells and an increase in the incidence of apoptosis of cancer cells in mice treated with either GSK-3beta inhibitor. No adverse events or effects were observed in the rodents during the course of treatment, except for rare lethal accidents due to intraperitoneal injection. Morphological examination showed no apparent pathologic changes in major organs including the lungs, liver, pancreas, kidneys, spleen and large bowel of rodents treated with DMSO and the GSK-3beta inhibitors. The results indicate that the GSK-3beta inhibitors would be a novel class of therapeutic agent for colon cancer.

Solid tumors subsequent to arsenic trioxide treatment for acute promyelocytic leukemia.

Arsenic trioxide (As(2)O(3)) is highly efficacious for acute promyelocytic leukemia (APL). Environmental arsenic exposure predisposes to malignancies, but the risk for therapeutic arsenic is undefined. Three APL patients (de novo, 2; therapy-related, 1) in a cohort of 59 cases given oral-As(2)O(3) for induction and maintenance treatment developed secondary cancers (nasopharyngeal carcinoma, 2; colonic adenocarcinoma, 1) at 16, 36 and 55 months post-As(2)O(3) therapy. Retrospective analysis of biomarkers (Epstein Barr virus serology and quantification, carcinoembryonic antigen) showed the potential presence of cancers before or shortly after As(2)O(3) therapy, suggesting that As(2)O(3) had not initiated these malignancies. Compared against matched background population, there was an increased risk of second cancer (p=0.012, standard incidence ratio=6.5; 95% confidence interval=1.4-19.0).

Mitotic catastrophe as a consequence of chemotherapy.

According to a widespread model, anti-cancer chemotherapy involves the triggering of tumor cells to undergo apoptosis, so apoptosis-resistant cells would be recalcitrant to such therapy. However, in addition to apoptosis, which is mainly dependent on the activity of the tumor suppressor protein p53, cells can be eliminated following DNA damage by other mechanisms. Mitotic catastrophe, a form of cell death that results from abnormal mitosis, is one such mechanism. While the term mitotic catastrophe has been used to describe a type of cell death that occurs during mitosis, there is still no broadly accepted definition. Occasionally, mitotic catastrophe is used restrictively for abnormal mitosis leading to cell death, which can occur through necrosis or apoptosis, rather than cell death itself. Although different classes of cytotoxic agents induce mitotic catastrophe, the pathways of abnormal mitosis differ depending on the nature of the inducer and the status of cell-cycle checkpoints. Moreover, mitotic catastrophe can also develop because of aberrant re-entry of tumor cells into the cell cycle after prolonged growth arrest. Elucidation of the factors that regulate different aspects of treatment-induced mitotic catastrophe should assist in improving the efficacy of anti-cancer therapy, providing opportunities for the development of new drugs.

Tratamiento de la erupción acneiforme por inhibidores del factor de crecimiento epidérmico con tetraciclinas orales / Treatment of acneiform rash by epidermal growth factor inhibitors with oral tetracyclines

Introducción. Los inhibidores del factor de crecimiento epidérmico (EGFR) son unos nuevos agentes antineoplásicos en creciente desarrollo. Se utilizan fundamentalmente como tratamiento de segunda línea de tumores en estadios avanzados. La aparición de una erupción acneiforme facial en pacientes tratados con estos fármacos es frecuente y característica. La literatura propone múltiples opciones de tratamiento, tanto tópico como sistémico. Hasta el momento, no hay una evidencia clara sobre ninguno de ellos. Pacientes y métodos. Realizamos un estudio descriptivo de 6 pacientes que han sido tratados con doxiciclina en dosis de 100 mg diarios durante 3 semanas. Analizamos las características clínicas de los pacientes y la eficacia del tratamiento. Resultados. Cinco de los seis pacientes alcanzan la curación total de la erupción acneiforme con este tratamiento. Un paciente alcanza una respuesta parcial. Tras largos períodos de seguimiento, y a pesar de continuar el tratamiento con los inhibidores del EGFR, no se observa recaída. Conclusiones. La doxicilina se plantea como un tratamiento eficaz en esta patología. A pesar de ser una serie corta, los resultados en nuestros pacientes avalan dicha eficacia

Introduction. Epidermal growth factor inhibitors (EGFR) are new antineoplastic agents that are increasingly being developed. They are basically used as second line treatment in advanced stage tumors. Appearance of a facial acneiform rash in patients treated with these drugs is common and characteristic. The literature proposes multiple topical and systemic treatment options. Up to now, there is no clear evidence on any of them. Patients and methods. A descriptive study of 6 patients who were treated with 100 mg daily dose of doxyclycline for 3 weeks was conducted. Clinical characteristics of the patients and treatment efficacy were analyzed. Results. Five of the six patients achieved total resolution of the acneiform rash with this treatment. One patient achieved partial response. After long follow-up periods and in spite of following treatment with the EGFR inhibitors, no relapse was observed. Conclusions. Doxycycline is suggested as an effective treatment in this disease. Even though it is a short series, the results in our patients support this efficacy

Effects of genistein, an isoflavone, on pregnancy outcome and organ weights of pregnant and lactating rats and development of their suckling pups.

There is a general agreement that isoflavones can be beneficial to health in adults. However, isoflavones are well known as endocrine-disrupting chemicals. It should be considered that soy foods might adversely affect the reproductive system and infants. The aim of this study was to evaluate the effects of genistein, an isoflavone, on dams and their offspring. Maternal rats were fed diets containing genistein at levels of 0 and 0.5 g/kg diet from pregnancy day 5 to postnatal day 13. No effects of genistein on the delivery, anogenital distance, reproductive organ weight, and body weight of the infants at birth were observed. There were no consistent effects on suckling pups after continuous genistein exposure during their fetal and suckling stages through their mothers, and there was no difference in effects according to the periods of exposure during pregnancy and lactation. We also observed no significant effect on the growth of offspring after weaning. Moreover, while we observed that the serum concentration of triiodothyronine (T3) in dams decreased, the result was a tendency, not a significant decrease. Our study suggested that maternal ingestion of genistein might have not induced serious adverse effects on dams, fetuses, infants or offspring during growth. However, the results indicated in many papers suggest the necessity of further study on the safety of genistein.

Erupción acneiforme por inhibidores del receptor de crecimiento epidérmico / Acneiform eruption from epidermal growth factor receptor inhibitors

Uno de los objetivos fundamentales de la investigación oncológica es la búsqueda de moléculas con mayor eficacia antitumoral y menor toxicidad que los agentes quimioterápicos habituales. Los inhibidores del receptor de crecimiento epidérmico son un nuevo grupo de fármacos que, por su efecto más específico frente a las células neoplásicas, parecen cumplir estas características. Entre los efectos adversos asociados a su uso, destacan por su frecuencia las erupciones cutáneas, secundarias a un efecto inhibitorio directo del fármaco sobre la homeostasis de la epidermis y del folículo pilosebáceo 1,2. Recientemente se han publicado varios casos de toxicidad cutánea en pacientes tratados con inhibidores del receptor de crecimiento epidérmico. Presentamos 3 casos de erupciones acneiformes atribuibles a diferentes fármacos de esta familia (cetuximab, gefitinib y erlotinib)

One of the fundamental aims of oncological research is the search for molecules with greater efficacy against tumors and less toxicity than the usual chemotherapeutic agents. Epidermal growth factor receptor inhibitors are a new group of drugs which, because of their more specific effect against neoplastic cells, seem to meet these characteristics. Skin eruptions are one of the most frequent adverse effects associated with their use, secondary to the drug's direct inhibitory effect on homeostasis of the epidermis and of the pilosebaceous follicle. Several cases of cutaneous toxicity in patients treated with epidermal growth factor receptor inhibitors have recently been published. We present three cases of acneiform eruptions attributable to different drugs in this family (cetuximab, gefitinib and erlotinib)

Drug-eluting stent: a review and update.

The development of stent has been a major advance in the treatment of obstructive coronary artery disease since the introduction of balloon angioplasty. However, neointimal hyperplasia occurring within the stent leading to in-stent restenosis is a main obstacle in the long-term success of percutaneous coronary intervention (PCI). The recent introduction of drug-eluting stents (DES) contributes a major breakthrough to interventional cardiology. Many large randomized clinical trials using DES have shown a remarkable reduction in angiographic restenosis and target vessel revascularization when compared with bare metal stents. The results of these trials also appear to be supported by evidence from everyday practice and non-controlled clinical trials. However, the expanded applications of DES, especially in treating complex lesions such as left main trunk, bifurcation, saphenous vein graft lesions, or in-stent restenosis, are still under evaluation with ongoing studies. With the availability of different types of DES in the market, the issue of cost should not be a deterrent and DES will eventually be an economically viable option for all patients. The adoption of DES in all percutaneous coronary intervention may become a reality in the near future. In this review article, we summarize the recent development and progress of DES as well as compare and update the results of clinical trials.

Evaluation of DNA damage in patients with arsenic poisoning: urinary 8-hydroxydeoxyguanine.

The relationship between arsenic exposure and DNA damage in patients with acute or chronic arsenic poisoning was analyzed. Urinary 8-hydroxydeoxyguanine (8-OHdG) concentrations were measured as an indication of oxidative DNA damage. A remarkable increase in 8-OHdG in the urine was observed in 60% of 52 patients with acute arsenic poisoning from the accidental oral intake of the arsenic trioxide. This was two- to threefold higher than levels in normal healthy subjects (n = 248). There was a clear relationship between arsenic concentrations in urine after acute poisoning and elevated levels of 8-OHdG. Levels of urinary 8-OHdG returned to normal within 180 days after the acute arsenic poisoning event. In patients chronically poisoned by the consumption of well water with elevated levels of arsenate [As(V)], elevated 8-OHdG concentrations in urine were also observed. A significant correlation between the 8-OHdG levels and arsenic levels in the urine was observed in 82 patients with chronic poisoning. Thus, evidence of oxidative DNA damage occurred in acute arsenic poisoning by arsenite [As(III)] and in chronic arsenic poisoning by As(V). In chronic poisoning patients provided low-arsenic drinking water, evidence of DNA damage subsided between 9 months and 1 year after the high levels of arsenic intake were reduced. The initial level of arsenic exposure appeared to dictate the length of this recovery period. These data indicate that some aspects of chronic and acute arsenic poisoning may be reversible with the cessation of exposure. This knowledge may contribute to our understanding of the risk elevation from arsenic carcinogenesis and perhaps be used in a prospective fashion to assess individual risk.

Effects of growth factors and receptor blockade on gastrointestinal cancer.

The advent of recombinant peptide technology offers the potential to use one or several peptides to treat a variety of gastrointestinal conditions. However, although cell culture and animal models have shown proof of concept, we are still at a relatively early stage in translating their use to standard clinical practice. Similarly, peptide and non-peptide antagonists of growth factor receptors show great potential as novel antichemotherapy agents. However, their actual place in clinical practice has yet to be established.

Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial.

OBJECTIVE: To evaluate the efficacy and safety of leflunomide in comparison with methotrexate (MTX) on patients with rheumatoid arthritis (RA) in China. METHODS: Five hundred and sixty-six patients with active rheumatoid arthritis were randomly assigned to receive leflunomide at 20 mg once daily or MTX at 15 mg once weekly in a controlled trial. Five hundred and four patients completed the 12-week treatment and some patients continued the treatment for 24 weeks. RESULTS: Both leflunomide and MTX could improve the symptoms, signs, and joint function, but there were no changes in X-ray observations of patients with rheumatoid arthritis. In the leflunomide group, the overall rates of effectiveness at 12 weeks and 24 weeks were 86.94% and 92.31% respectively; the rates of remarkable improvement were 64.95% and 79.81% respectively. In the MTX group, the overall rates of effectiveness at 12 weeks and 24 weeks were 84.04% and 83.15% respectively; the rates of remarkable improvement were 56.81% and 75.28% respectively. According to intent-to-treat analysis, the ACR 20% response rates at 12 weeks and 24 weeks in the leflunomide group were 62.54% and 67.18% respectively, compared with 60.08% and 61.32% respectively in MTX group. No statistical differences were shown in the efficacy between the two groups (P > 0.05). The adverse events in the leflunomide group were gastrointestinal symptoms, skin rash, alopecia, nervous system symptoms, decreased leukocyte count, and elevation of alanine aminotransferase (ALT). Most of these side effects were mild and transient. The incidence of adverse events in the leflunomide group was 16.84%, significantly lower than that in MTX group (28.17%, P = 0.002). CONCLUSIONS: Leflunomide is effective in the treatment of RA with less adverse events than MTX. Its efficacy is similar to MTX, but the incidence of adverse events and the rate of withdrawal due to adverse events were lower in the leflunomide group than in MTX group.