DOES THE ASSOCIATION OF TACROLIMUS AND MYCOPHENOLATE MOFETIL CHANGE THE HEALING OF THE ABDOMINAL WALL? STUDY IN RATS SUBMITTED TO ISCHEMIA AND KIDNEY REPERFUSION.

BACKGROUND: Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants. AIM: To evaluate the influence of the association of them on the abdominal wall healing in rats. METHODS: Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination. RESULTS: There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups. CONCLUSION: The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.

Anti-fibrotic effect of mycophenolate mofetil on Peyronie's disease experimentally induced with TGF-ß.

The aim of the present study was to evaluate the histological, histochemical, and stereological changes caused by mycophenolate mofetil (MMF) on the tunica albuginea of rat penises submitted to an injection of transforming growth factor beta (TGF-ß) for the induction of Peyronie's disease (PD). Twenty adult male Wistar rats were divided into four groups: Control group; TGF-ß group (TGF-ß injection); MMF-7d group (treated with MMF 7 days after induction with TGF-ß); and MMF-30d group (treated with MMF 30 days after induction with TGF-ß). The steorological evaluation included the relative volume of different types of connective fibres of the tunica albuginea. The histochemical analysis revealed the fragmentation and degradation of elastin in the tunica albuginea. This process was partially reversed in the MMF-7d group and a situation very close to normality was observed in the MMF-30d group. In the collagen III/collagen I ratio it was observed increase in this ratio in the TGF-ß (59.4 ± 5.53) and MMF-7d (49 ± 18.2) groups and a decrease in the MMF-30d group (28.7 ± 4), approaching normality. The injection of TGF-ß promoted fibrotic alterations in the penile tunica albuginea in Wistar rats corresponding to PD. In this model, MMF acts as a regenerating anti-fibrotic agent.

Does the association of tacrolimus and mycophenolate mofetil change the healing of the abdominal wall? study in rats submitted to ischemia and kidney reperfusion / A associação de tacrolimus e micofenolato mofetil altera a cicatrização da parede abdominal? estudo em ratos submetidos à isquemia e reperfusão renal

ABSTRACT Background: Tacrolimus and mycophenolate mofetil are immunosuppressive agents widely used on the postoperative period of the transplants. Aim: To evaluate the influence of the association of them on the abdominal wall healing in rats. Methods: Thirty-six Wistar rats were randomly assigned in three groups of 12. On the early postoperative period, four of the control group and three of the experimental groups died. The three groups were nominated as follow: control group (GC, n=8); group I (GI, n=11, standard operation, mycophenolate mofetil and tacrolimus); group II (GII, n=10, standard operation, mycophenolate mofetil and tacrolimus). The standard operation consisted of right total nephrectomy and 20 min ischemia of the left kidney followed by reperfusion. Both NaCl 0.9% and the immunosuppressive agents were administered starting on the first postoperative day and continuing daily until the day of death on the 14th day. On the day of their deaths, two strips of the anterior abdominal wall were collected and submitted to breaking strength measurement and histological examination. Results: There were no significant differences in wound infection rates (p=0,175), in the breaking strength measurement and in the histological examination among the three groups. Conclusion: The combination of the immunosuppressive agents used in the study associated with renal ischemia and reperfusion does not interfere in the abdominal wall healing of rats.

RESUMO Racional: O tacrolimus e o micofenolato mofetil são imunossupressores amplamente utilizados no pós-operatório dos transplantes de órgãos. Objetivo: Avaliar os efeitos deles sobre a cicatrização da parede abdominal em ratos. Métodos: Foram utilizados 36 ratos Wistar, distribuídos aleatoriamente em três grupos de 12. No pós-operatório imediato, quatro do grupo controle e três do grupo experimentação morreram. Os três grupos receberam as seguintes denominações: grupo controle (GC, n=8); grupo I (GI, n=11, operação-padrão, micofenolato mofetil e tacrolimus); grupo II (GII, n=10, operação-padrão, micofenolato mofetil e tacrolimus). A operação-padrão consistiu de nefrectomia total à direita, isquemia durante 20 min seguida de reperfusão do rim esquerdo. Solução de NaCl 0,9% e micofenolato mofetil + tracolimus foram administradas a partir do 1° dia do pós-operatório e mantidas até o dia do sacrifício dos animais, no 14° dia. Na data do sacrifício, foram retirados dois fragmentos da parede abdominal para análise da resistência à ruptura e exame histológico. Resultados: Não houve diferença estatisticamente significativa no índice de infecção de ferida operatória (p=0,175), nos valores de resistência de ruptura e nos achados histopatológicos entre os três grupos de animais. Conclusão: Os esquemas de imunossupressão empregados associados ao fenômeno da isquemia-reperfusão renal não induzem fraqueza significativa da cicatriz da parede abdominal em ratos no 14° dia de pós-operatório.

Long-term Tolerance Toward Haploidentical Vascularized Composite Allograft Transplantation in a Canine Model Using Bone Marrow or Mobilized Stem Cells.

BACKGROUND: The development of safe and reliable protocols for the transplantation of the face and hands may be accomplished with animal modeling of transplantation of vascularized composite allografts (VCA). Previously, we demonstrated that tolerance to a VCA could be achieved after canine recipients were simultaneously given marrow from a dog leukocyte antigen-identical donor. In the present study, we extend those findings across a dog leukocyte antigen mismatched barrier. METHODS: Eight recipient dogs received total body irradiation (4.5 cGy), hematopoietic cell transplantation (HCT), either marrow (n = 4) or granulocyte-colony stimulating factor mobilized peripheral blood stem cells (n = 4), and a VCA transplant from the HCT donor. Post grafting immunosuppression consisted of mycophenolate mofetil (28 days) and cyclosporine (35 days). RESULTS: In 4 dogs receiving bone marrow, 1 accepted both its marrow transplant and demonstrated long-term tolerance to the donor VCA (>52 weeks). Three dogs rejected both their marrow transplants and VCA at 5 to 7 weeks posttransplant. Dogs receiving mobilized stem cells all accepted their stem cell transplant and became tolerant to the VCA. However, 3 dogs developed graft-versus-host disease, whereas 1 dog rejected its stem cell graft by week 15 but exhibited long-term tolerance toward its VCA (>90 weeks). CONCLUSIONS: The data suggest that simultaneous transplantation of mobilized stem cells and a VCA is feasible and leads to tolerance toward the VCA in a haploidentical setting. However, there is a higher rate of donor stem cell engraftment compared with marrow HCT and an increase in the incidence of graft-versus-host disease.

Anti-Inflammatory Therapy Modulates Nrf2-Keap1 in Kidney from Rats with Diabetes.

This study addressed the relationship of proinflammatory cytokines and Nrf2-Keap1 system in diabetic nephropathy. The experimental groups were control, diabetic, and diabetic treated with mycophenolate mofetil (MMF). The renal function, proinflammatory and profibrotic cytokines, oxidative stress, morphology, and nephrin expression were assessed. Diabetic group showed impaired renal function in association with oxidative stress and decreased Nrf2 nuclear translocation. These results were associated with increased mesangial matrix index, interstitial fibrosis, and increased nephrin expression in cortex and urine excretion. Additionally, interleukin-1ß, IL-6, and transforming growth factor-ß1 were increased in plasma and kidney. MMF treatment conserved renal function, prevented renal structural alterations, and partially prevented the proinflammatory and profibrotic cytokines overexpression. Despite that MMF treatment induced nephrin overexpression in renal tissue, preventing its urinary loss. MMF salutary effects were associated with a partial prevention of oxidative stress, increased Nrf2 nuclear translocation, and conservation of antioxidant enzymes in renal tissue. In conclusion, our results confirm that inflammation is a key factor in the progression of diabetic nephropathy and suggest that treatment with MMF protects the kidney by an antioxidant mechanism, possibly regulated at least in part by the Nrf2/Keap1 system, in addition to its well-known anti-inflammatory effects.

Effects of mycophenolate sodium on mucociliary clearance using a bronchial section and anastomosis rodent model.

OBJECTIVE: To study the effects of mycophenolate sodium on mucociliary clearance. INTRODUCTION: Mycophenolate is one of the most commonly used immunosuppressive drugs in lung transplantation. Although its pharmacokinetic properties are well defined, its side effects on mucociliary clearance have not yet been studied. METHODS: Sixty rats were subjected to left bronchial section and anastomosis. The right bronchus was used as a control. After surgery, the rats were assigned to two groups based on whether they received saline solution (n = 30) or mycophenolate sodium (n = 30). After 7, 15, or 30 days of treatment, 10 animals from each group were sacrificed, and in vitro mucus transportability, in situ mucociliary transport velocity and ciliary beat frequency were measured. RESULTS: The analysis of mucus transportability revealed that neither mycophenolate nor bronchial section altered any transportability related property for up to 30 days of treatment after surgery (p>0.05). With regard to ciliary beat frequency, the operated left bronchi from the mycophenolate group showed a significant decrease on post-surgical day 30 (p = 0.003). In addition, we found a significant reduction in the in situ mucociliary transport velocity in the mycophenolate-treated group (p = 0.0001). DISCUSSION: These data add important information regarding mucociliary clearance dysfunction following mycophenolate therapy and suggest that mycophenolate might contribute to the high incidence of respiratory tract infections in lung transplant patients. Further studies are needed to investigate the combined action of mycophenolate with other immunosuppressive drugs and to establish methods to protect and recover mucociliary clearance, an important airway defense mechanism.

Evidence of an anti-inflammatory effect of mycophenolate mofetil in a murine model of pleurisy.

A promising therapeutic approach to reducing inflammation is to inhibit the production of proinflammatory cytokines (e.g., tumor necrosis factor alpha [TNF-α], interleukin 1 beta [IL-1ß], vascular endothelial growth factor alpha (VEGF-α), and, as shown more recently, interleukin-17 [IL-17]). In the present study, the authors have demonstrated the anti-inflammatory effects of mycophenolate mofetil (MMF) in in vivo experiments and have investigated the mechanism of action underlying those effects. Oral administration of MMF significantly inhibited leukocyte influx during the first (4 hours) and second (48 hours) phases of inflammation in a mouse model of pleurisy caused by carrageenan (P < .01). As expected, MMF suppressed protein levels of TNF-α, IL-1ß, VEGF-α, and IL-17A (P < .01). This inhibitory effect was due to down-regulation of mRNA expression for these proinflammatory cytokines (P < .01). These results provide evidence of MMF-mediated inhibition of proinflammatory cytokines, and these anti-inflammatory effects are assumed to result mainly from the inhibition of the synthesis and release of TNF-α, IL-1ß, VEGF-α, and IL-17A from activated leukocytes. These findings suggest that MMF might be an applicable therapeutic in the regulation of the inflammatory response-a response in which the humoral system plays a pivotal role.

Effects of mycophenolate sodium on mucociliary clearance using a bronchial section and anastomosis rodent model

OBJECTIVE: To study the effects of mycophenolate sodium on mucociliary clearance. INTRODUCTION: Mycophenolate is one of the most commonly used immunosuppressive drugs in lung transplantation. Although its pharmacokinetic properties are well defined, its side effects on mucociliary clearance have not yet been studied. METHODS: Sixty rats were subjected to left bronchial section and anastomosis. The right bronchus was used as a control. After surgery, the rats were assigned to two groups based on whether they received saline solution (n = 30) or mycophenolate sodium (n = 30). After 7, 15, or 30 days of treatment, 10 animals from each group were sacrificed, and in vitro mucus transportability, in situ mucociliary transport velocity and ciliary beat frequency were measured. RESULTS: The analysis of mucus transportability revealed that neither mycophenolate nor bronchial section altered any transportability related property for up to 30 days of treatment after surgery (p>0.05). With regard to ciliary beat frequency, the operated left bronchi from the mycophenolate group showed a significant decrease on post-surgical day 30 (p = 0.003). In addition, we found a significant reduction in the in situ mucociliary transport velocity in the mycophenolate-treated group (p = 0.0001). DISCUSSION: These data add important information regarding mucociliary clearance dysfunction following mycophenolate therapy and suggest that mycophenolate might contribute to the high incidence of respiratory tract infections in lung transplant patients. Further studies are needed to investigate the combined action of mycophenolate with other immunosuppressive drugs and to establish methods to protect and recover mucociliary clearance, an important airway defense mechanism.

Antioxidant effects of mycophenolate mofetil in a murine pleurisy model.

Generation of oxidative stress induced by reactive oxygen species (ROS) and nitrogen (RNS) is believed to be a primary factor in the etiology of various inflammatory diseases. Although, the process of generation of oxygen species is a physiological event, in the inflammatory process this event is increased and produces large amounts of reactive species that leads to lipid peroxidation and to cell death. Mycophenolate mofetil (MMF) is a drug effective in protecting against chronic allograft failure and recently was introduced as an alternative for the treatment of various inflammatory diseases such as glomerulopathies, systemic lupus erythematosus and systemic vasculitis. Based on studies of the anti-inflammatory effect of MMF the aim of this study was to evaluate the effects of MMF on the inhibition of leukocytes and exudation, as well as myeloperoxidase and some antioxidant enzyme activities using carrageenan-induced pleurisy in mice. Our results showed that MMF significantly decreased leukocyte influx (P<0.01), exudation (P<0.01), superoxide dismutase (P<0.05), catalase (P<0.05), glutathione peroxidase (P<0.01), glutathione S-transferase (P<0.01) activities, levels of lipid peroxidation (P<0.05), as well as myeloperoxidase activity (P<0.05) on both phases (4h and 48h) of the inflammatory response induced by carrageenan into the mice pleural cavity. In conclusion, the anti-inflammatory effect of MMF may be, at least in part, via inhibition of ROS and/or NRS overgeneration, and consequently, attenuating the related oxidative stress.

Immunosuppressive drugs have different effect on B lymphocyte subsets and IgM antibody production in immunized BALB/c mice.

Infections are frequently associated with immunosuppressive therapy currently used to prevent organ rejection or treat autoimmune diseases. Such drugs suppress antibody production despite having different mechanisms of action. Antibodies are produced by a non-homogenous population of B lymphocyte subsets. B-1 cells produce natural antibodies and protect immediately after infection, while B2 cells produce antigen-specific IgM antibodies in a later response to infection. To understand how the immunosuppressive drugs affect antibody production by B cell populations, we immunized BALB/c mice with different antigens followed by administration of various immunosuppressive drugs. B-1a and B-1b lymphocytes from spleens of sacrificed animals were analyzed by flow cytometry, natural and antigen -specific IgG and IgM antibodies were determined by nephelometry and ELISA assays. Results showed that prednisone (PDN), cyclophosphamide (CYC), methotrexate (MTX), mycophenolate mofetil (MMF) and azathioprine (AZA) decreased more than 60% of B-1a lymphocytes while cyclosporine (CsA) had little effect. Three drugs PDN, AZA and CYC suppressed the B-2 cells on day 30, while MTX affected this subpopulation early on day 5. Antigen-specific IgM antibodies were dramatically suppressed after 15 days of immunization in animals receiving PDN, CYC or AZA, while MMF, CsA and MTX showed little effect. Natural antibodies were equally decreased in all animals regardless of the specific drug used in treatment. These results will help to choose single or combinations of immunosuppressive drugs in the clinical setting.

Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus.

This study was conducted to evaluate time-dependent pharmacokinetic changes and drug interactions over the first 6 months after transplantation in kidney transplant recipients receiving tacrolimus (TAC), prednisone (PRED) and mycophenolate mofetil (MMF) or sirolimus (SRL). Pharmacokinetic assessments were carried out at day 7 and months 1, 3, and 6 in kidney transplant recipients receiving TAC plus PRED with either MMF (2 g/day, n = 13) or SRL (15 mg loading dose, 5 mg for 7 days followed by 2 mg/day, n = 12). There were no differences in the main demographic characteristics or in mean PRED doses during the first 6 months after transplant. From day 7 to month 6, there was a 65% increase in TAC dose corrected exposure (dose corrected area under the curve; AUC) in patients receiving MMF (P = 0.005) and a 59% increase in TAC dose corrected exposure in patients receiving SRL (P = 0.008). From day 7 to month 6, there was a 72% increase in mycophenolate dose corrected exposure (P = 0.001) and a 65% increase in SRL dose corrected exposure (P = 0.008). TAC dose corrected exposure was 23% lower in patients receiving SRL compared with MMF (P = 0.012) on average over the study period. PRED dose reduction was associated with increase in TAC (in patients receiving SRL, P = 0.040) and mycophenolic acid (MPA) (P = 0.070) drug exposures. Tercile distribution of TAC drug exposure showed a positive correlation with mean SRL exposures (P = 0.016). Conversely, tercile distribution of SRL drug exposure showed a positive correlation with mean TAC exposures (P = 0.004). Time-dependent increases in TAC, MPA and SRL drug exposures occur up to 6 months after transplantation. Drug-to-drug interactions indicate that intense therapeutic drug monitoring is required to avoid under- or over-immunosuppression.

[Effects of mycophenolate mofetil in ischemic acute renal failure in rats]. / Efectos del micofenolato mofetil en la insuficiencia renal aguda isquémica en ratas.

Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic insult may reduce the severity of histologic damage resulting from ischemia reperfusion injury.

Mycophenolate mofetil administration reduces renal inflammation, oxidative stress, and arterial pressure in rats with lead-induced hypertension.

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Renal angiotensin II concentration and interstitial infiltration of immune cells are correlated with blood pressure levels in salt-sensitive hypertension.

Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with (n = 10) and without (n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- (n = 7) and normal (n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean +/- SD) low plasma (2.4 +/- 1.4 pg/ml) and high interstitial AII concentration (1,310 +/- 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 +/- 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.

Mycophenolate mofetil reduces disease activity and steroid dosage in Takayasu arteritis.

Mycophenolate mofetil (MMF) has recently been reported as a useful alternative immunosuppressive drug in autoimmune diseases including in Takayasu arteritis (TA). The aim of this study was to verify the efficacy and tolerability of MMF administration in controlling TA disease activity and allowing glucocorticosteroid reduction. Ten consecutive active TA patients followed at the Vasculitis Clinic were enrolled from January 2003 to 2006 and received oral MMF (2 g/day) for an average of 23.3 months. Disease activity assessed using the National Institutes of Health criteria, clinical features, and inflammatory laboratory findings were evaluated. Five patients had received at least one immunosuppressive drug before administration of MMF (four methotrexate, two azathioprine, and one chlorambucil) but had not achieved clinical and laboratory remission. The other five patients received MMF as their first immunosuppressive drug because of an important disease flare during steroid dose reduction. Clinical activity disappeared in all patients with MMF therapy, except in one patient who abandoned the study because of an important headache, attributed to the drug. Moreover, the MMF therapy allowed significant tapering of the prednisone dose in the rest of the nine patients (24.5 +/- 17.1 vs 5.8 +/- 7.8 mg/day; p = 0.0019). Reinforcing this finding, a significant reduction in inflammatory laboratory parameters, erythrocyte sedimentation rate (24.7 +/- 15.5 vs 12.8 +/- 10.8 mm/h; p = 0.036) and C-reactive protein (24.0 +/- 14.9 vs 11.2 +/- 10.7 mg/l; p = 0.0167), was observed. In summary, MMF therapy reduced clinical and laboratory parameters of TA disease activity, suggesting that this drug is a promising immunosuppressive drug, particularly in refractory cases and as a steroid-sparing agent.

In vitro study of antiviral activity of mycophenolic acid on Brazilian orthobunyaviruses.

OBJECTIVE: Oropouche, Caraparu, Guama, Guaroa and Tacaiuma are ssRNA viruses that belong to the genus Orthobunyavirus and have been associated with human febrile illnesses and/or encephalitis. In this study, we evaluated the antiviral action of mycophenolic acid (MPA) on theseorthobunyaviruses to achieve a therapeutic agent to treat the diseases caused by these viruses. METHODS: The in vitro antiviral evaluation to MPA was done by using plaque assay at different periods of treatment. RESULTS: Results showed that MPA at a concentration of 10 microg/ml has significant antiviral activity on Tacaiuma virus when treatment was initiated either 24 h before or 2 h after viral infection. Moreover, MPA has an inhibitory effect on Guama virus replication, but only when treatment was initiated before cell infection. Addition of guanosine in the culture reverted the inhibitory effect of MPA on Tacaiuma and Guama viruses, suggesting that the antiviral activity of this substance was via depletion of the intracellular guanosine pool. CONCLUSION: Our results suggest that MPA would not be a good therapeutic agent to treat the diseases caused by Oropouche, Caraparu, Guama, Guaroa, and Tacaiuma viruses.

IMPACT Trial: angiographic and intravascular ultrasound observations of the first human experience with mycophenolic acid-eluting polymer stent system.

The purpose of the study was to examine the safety and efficacy of two different formulations of mycophenolic acid (MPA)-eluting Duraflex stents on coronary de novo lesions. Recent data indicate that local delivery of MPA in the porcine overstretch coronary model significantly reduces neointimal hyperplasia (NIH). Patients were divided into three consecutive groups. The first (n=50) and second (n=55) groups received moderate- and slow-release MPA-eluting Duraflex stent, respectively. The last group (n=50) received the bare metal Duraflex stent. Clinical, angiographic, and intravascular ultrasound analysis were performed at 6-month follow-up. All stents were successfully deployed and patients were discharged home without clinical events. Compared to controls, 6-month in-lesion and in-stent minimum luminal diameter as well as late lumen loss were not significantly different in the moderate- and slow-release treatment groups. At follow-up, percentage obstruction and NIH volume were also similar between the three groups. At 30 days and 6 and 12 months, there were no differences noted between the three groups with respect to major adverse cardiac events as well as the individual rates of mortality, myocardial infarction, or repeat revascularization. There were no cases of subacute or late thrombosis. In this feasibility trial, the MPA-eluting Duraflex stents in either slow- or moderate-release formulations were well tolerated, but showed no benefit for treatment of coronary lesions when compared to controls. Further testing with different drug dosing or delivery rate might improve these results.

Mycophenolate mofetil ameliorates nephropathy in the obese Zucker rat.

BACKGROUND: The obese Zucker rat has metabolic condition resembling type II diabetes, including hyperlipidemia, obesity, insulin resistance, and hyperglycemia. With advancing age, the obese Zucker rat develops glomerulosclerosis, proteinuria, and renal failure. Since immune cells play a central role in the development of chronic renal injury, we evaluated the potential benefit of mycophenolate mofetil (MMF), alone and in combination with angiotensin receptor type 1 blockade (ARB) in the obese Zucker rat. METHODS: Thirteen-week-old male obese Zucker rats (fa/fa) were randomly assigned to four experimental groups (five rats each) that received the following treatments for 3 months: (1) losartan (100 mg/L in the drinking water), (2) MMF (20 mg/kg/day), (3) MMF and losartan, and (4) placebo. Lean Zucker rats (N = 5) were included as normal controls. Renal function, biochemical parameters, renal histology, and immunohistology were evaluated. RESULTS: The placebo-treated obese Zucker rats exhibited proteinuria and significant glomerular and tubulointerstitial injury in association with renal immune cell infiltration. Proteinuria, histologic damage, and renal immune cell infiltration were all reduced by MMF treatment alone or in combination with ARB. The improvement of proteinuria and structural damage was more pronounced in the group that received the combination of MMF and losartan. CONCLUSION: MMF treatment alone, and especially in combination with ARB, improves nephropathy in the obese Zucker rat.

Hypertension in Page (cellophane-wrapped) kidney is due to interstitial nephritis.

BACKGROUND: Cellophane wrapping of the kidneys (Page kidney) induces perinephrits and hypertension, assumed to be due to renal ischemia resulting from parenchymal compression by the fibrous hull surrounding the kidneys. We investigated if interstitial nephritis, rather than plasma angiotensin activity, played a role in the development of hypertension in the Page kidney model. METHODS: We followed for 7 weeks rats with bilateral cellophane wrapping of the kidneys that received 20 mg/kg/day of the immunosuppressive antiproliferative drug mycophenolate mofetil (MMF) (two-kidney wrap/MMF) (N = 10) or vehicle (two-kidney wrap) (N = 10), and sham-operated rats (N = 10). RESULTS: The two-kidney wrap group had progressive increment in blood pressure, inflammatory damage occupying 25% to 50% of the renal tubulointerstitial region and increased number of angiotensin II-positive cells, angiotensin II content, and oxidative stress in the kidney. MMF treatment prevented the development of hypertension and renal inflammation without modifying the perinephritic hull or the increment it induced in the intrarenal pressure. The plasma levels of angiotensin II were similar in the two-kidney wrap group, the two-kidney wrap/MMF group and the sham-operated animals and unchanged from baseline, despite the blood pressure increase in the two-kidney wrap group. CONCLUSION: Our results indicate that renal wrap hypertension is unrelated to plasma angiotensin II levels and related to the inflammatory damage caused by the external compression of the kidney.