Astragalus membranaceus and Salvia miltiorrhiza ameliorates cyclosporin A-induced chronic nephrotoxicity through the "gut-kidney axis".

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Astragalus membranaceus and Salvia miltiorrhiza (AS) is an effective prescription that is widely used to treat chronic kidney disease (CKD) clinically in traditional Chinese medicine. Our previous studies have shown that AS can alleviate early CKD through the "gut-kidney axis", but the regulatory role of AS in the "gut-kidney axis" in the middle and late stages of CKD caused by cyclosporin A-induced chronic nephrotoxicity (CICN) has remained unclear. AIM OF THE STUDY: To explore the protective effect of AS by regulating the intestinal flora to further control the miRNA-mRNA interaction profiles in CICN. MATERIALS AND METHODS: Thirty-two mice were divided into four groups: Normal (N) (olive oil), Model (M) (CsA, 30 mg kg-1 d-1), AS (CsA + AS, 30 + 8.4 g kg-1 d-1) and FMT-AS (CsA + Faeces of AS group, 30 mg + 10 mL kg-1 d-1). The mice were treated for 6 weeks. Changes in renal function related metabolites were detected, pathological changes in the colon and kidney were observed, and 16S rDNA sequencing was performed on mouse faeces. In addition, miRNA and mRNA sequencing were performed on the kidney to construct differential expression (DE) profiles of the other 3 groups compared with group M. The target mRNAs among the DE miRNAs were then predicted, and an integrated analysis was performed with the DE mRNAs to annotate gene function by KEGG. DE miRNAs and DE mRNAs related to CICN in the overlapping top 20 KEGG pathways were screened and verified. RESULTS: Eight metabolites that could worsen renal function were increased in group M, accompanied by thickening of the glomerular basement membrane, vacuolar degeneration of renal tubules, and proliferation of collagen fibres, while AS and FMT-AS intervention amended these changes to varying degrees. Simultaneously, intestinal permeability increased, the abundance and diversity of the flora decreased, and the ratio of Firmicum to Bacteroides (F/B) increased in group M. The AS and FMT-AS treatments reversed the flora disorder and increased probiotics producing butyric acid and lactic acid, especially Akkermansia and Lactobacillus, which might regulate the 12 overlapping top 20 KEGG pathways, such as Butanoate metabolism, Tryptophan metabolism and several RF-related pathways, leading to the remission of renal metabolism. Finally, 15 DE miRNAs and 45 DE mRNAs were screened as the therapeutic targets, and the results coincided with the sequencing results. CONCLUSION: AS could alleviate renal fibrosis and metabolism caused by CICN through the "gut-kidney axis". Probiotics such as Akkermansia and Lactobacillus were the primary driving factors, and the miRNA-mRNA interaction profiles, especially Butanoate metabolism and Tryptophan metabolism, may be an important subsequent response and regulatory mechanism.

Schisandrae chinensis fructus extract protects against hepatorenal toxicity and changes metabolic ions in cyclosporine A rats.

While cyclosporin A (CsA) is an effective immunosuppressive agent, its clinical application is limited by serious hepatorenal toxicity. However, Schisandrae chinensis fructus extract (SCE) has been previously shown to alleviate the hepatorenal damage caused by CsA. In this study, we aimed to evaluate the protective effects of SCE against hepatorenal toxicity induced by CsA. Our results revealed that SCE can prevent and treat CsA-induced liver and kidney injury. Furthermore, SCE inhibited the upward trend of dUDP and CDP-ethanolamine in the urine of CsA rats, pathways of which are involved in pyrimidine and glycerophospholipid metabolism. We finally confirmed that this protection of SCE was regulated by the activation of Nrf2 signaling pathway and the inhibition of apoptosis. In summary, our findings indicated that SCE may effectively prevent and treat hepatorenal toxicity caused by CsA. In addition, metabolomic techniques identified potential biomarkers for the occurrence of hepatorenal toxicity in CsA rats.

Cyclosporine A induces testicular injury via mitochondrial apoptotic pathway by regulation of mir-34a and sirt-1 in male rats: The rescue effect of curcumin.

Testicular damage contributes to cyclosporine A (CsA) induced male infertility. However, the exact underlying molecular mediators involved in CsA-induced testis disorder remains unclear. The present study aimed to characterize the role of mir-34a/sirt-1 in CsA induced testicular injury alone or in combination with curcumin. A total of twenty-eight male Wistar rats were subdivided into four groups: control (Con), sham, cyclosporine A (CsA), cyclosporineA + curcumin (CsA + cur). The animals received cyclosporine A (30 mg/kg) and curcumin (40 mg/kg) for 28 days by oral gavage. At the end of the experiment, CsA administration significantly resulted in a decrease in testis weight and testis coefficient. The molecular analysis demonstrated that CsA exposure increased 8-OHdg and Nox4 protein contents in the testis tissue. TUNEL staining indicated that CsA caused the number of apoptotic cells to increase in the testes of male rats. In addition, exposure to CsA resulted in an increased expression of Bax, and a decreased expresion in that of Bcl-2, with a concomitant up-regulation of the Bax/Bcl-2, c-Caspase-3/p-Caspase-3 ratio and cytochrome c level. Meanwhile, exposure to CsA increased the expression of mir-34a and decreased sirt-1 protein level in the testis tissue samples compared to the control group. Taken together, our findings suggested that CsA can cause damage to testicular germ cells via oxidative stress and mitochondrial apoptotic pathway, and probably mir-34a/sirt-1 play a crucial role in this process. It also demonstrates that these negative effects of CsA can be reduced by using curcumin as an antioxidant and anti-inflammatory agent.

Effective reconstruction of functional organotypic kidney spheroid for in vitro nephrotoxicity studies.

Stable and reproducible kidney cellular models could accelerate our understanding of diseases, help therapeutics development, and improve nephrotoxicity screenings. Generation of a reproducible in vitro kidney models has been challenging owing to the cellular heterogeneity and structural complexity of the kidney. We generated mixed immortalized cell lines that stably maintained their characteristic expression of renal epithelial progenitor markers for the different lineages of kidney cellular compartments via the BMP7 signaling pathway from a mouse and a human whole kidney. These cells were used to generate functional and matured kidney spheroids containing multiple renal lineages, such as the proximal tubule, loop of Henle, distal tubules, and podocytes, using extracellular matrix and physiological force, named spheroid-forming unit (SFU). They expressed all apical and basolateral transporters that are important for drug metabolism and displayed key functional aspects of the proximal tubule, including protein endocytosis and increased gamma-glutamyltransferase activity, and cyclic AMP responded to external cues, such as parathyroid hormone. Following exposure, cells fluxed and took up drugs via proximal tubule-specific apical or basolateral transporters, and displayed increased cell death and expression of renal injury marker. Here, we developed a new differentiation method to generate kidney spheroids that structurally recapitulate important features of the kidney effectively and reproducibly using mixed immortalized renal cells, and showed their application for renal toxicity studies.

Omega-3 fatty acid decreases oleic acid by decreasing SCD-1 expression in the liver and kidney of a cyclosporine-induced nephropathy rat model.

AIM: Stearoyl-CoA desaturase (SCD)-1 and elongase-6 (Elovl-6) are associated with fatty acid (FA) synthesis. We evaluated the effect of omega-3 FA on erythrocyte membrane FA contents through SCD-1 and Elovl-6 expression in the liver and kidney of a cyclosporine (CsA)-induced rat model. METHODS: Male Sprague Dawley rats were divided into control, CsA, and CsA treated with omega-3 FA groups. We measured SCD-1 and Elovl-6 expression levels via western blot and immunohistochemistry analysis. RESULTS: Erythrocyte membrane oleic acid content was lower in the CsA with omega-3 FA group compared to the CsA group. Compared to the control group, CsA-induced rats showed elevated SCD-1 expression in the kidney and liver, which omega-3 FA treatment reversed. Elovl-6 expression was increased in the liver, but decreased in the kidney in CsA group compared to control, which omega-3 FA treatment also reversed. CONCLUSIONS: Omega-3 FA supplementation decreased erythrocyte membrane oleic acid content by modulating SCD-1 and Elovl-6 expression in the kidney and liver of CsA-induced rats.

Upregulation of cystathionine-γ-lyase/hydrogen sulfide pathway underlies the celecoxib counteraction of cyclosporine-induced hypertension and renal insult in rats.

We recently reported that celecoxib, a selective cyclooxygenase-2 (COX2) inhibitor, counteracts the adverse circulatory and renal actions of cyclosporine (CSA). Despite the seemingly advantageous nature of this interaction particularly in clinical settings that necessitate the combined use of the two drugs such as immune-related arthritis, the underlying mechanism remains elusive. This prompted us to test the hypothesis that the facilitation of the cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) signaling accounts for such favorable effects of celecoxib on CSA nephrotoxicity. The data showed that the 10-day co-treatment of rats with celecoxib (10 mg/kg/day) ameliorated the hypertensive and biochemical and renal structural damages caused by CSA (20 mg/kg/day). Celecoxib also reversed the CSA-evoked (i) reductions in the tubular and glomerular protein expression of CSE and levels of H2S, prostaglandin E2 (PGE2), and total antioxidant capacity (TAC), and (ii) increases in inflammatory (tumor necrosis factor-α, TNF-α), fibrotic (transforming growth factor-ß1, TGF-ß1) and apoptotic (caspase-3) cytokines. These celecoxib effects disappeared when rats were treated concomitantly with the CSE inhibitor DL-propargylglycine (DL-PAG), indicating the importance of the CSE-derived H2S in mediating the renoprotective action of celecoxib. This view is bolstered by the observation that the beneficial hemodynamic and renal actions of celecoxib were replicated after supplementation of rats with sodium sulfide (Na2S, H2S donor). Together, the increased abundance of renal CSE and H2S and subsequent dampening down of inflammatory, fibrotic, oxidant, and apoptotic pathways play pivotal roles in the capacity of celecoxib to compromise the troublesome hypertensive and nephrotoxic insults caused by CSA in rats.

Attenuation of cyclosporine A induced nephrotoxicity by schisandrin B through suppression of oxidative stress, apoptosis and autophagy.

Cyclosporine A (CsA) is a potent immunosuppressive agent whose clinical usage is limited by nephrotoxicity. Schisandrin B (SchB), isolated from the fruit of Schisandra chinensis, is a natural compound with multiple pharmacological activities that has been shown to attenuate organ injury caused by CsA. Hence, the primary objective of the current study was to evaluate whether SchB has a cytoprotective effect on CsA-induced nephrotoxicity in human proximal tubular epithelial cell line (HK-2). This study demonstrated that pre-incubation of HK-2 cells with 2.5-10.0µM SchB ameliorated CsA induced cytotoxicity caused by oxidative stress as evidenced by reduced levels of intracellular reactive oxygen species (ROS) and LDH release along with increased levels of mitochondrial membrane potential (ΔΨm) and glutathione (GSH). Also, it was demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) activation was involved in modulating cellular oxidative stress, where SchB promoted Nrf2 translocation into the nucleus and downstream target gene expression of heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and Glutamate-cysteine ligase modifier subunit (GCLM). Additionally, SchB was found to enhance cell survival via reducing apoptosis rate as well as recover the CsA induced blockade of autophagic flux. Collectively, these findings demonstrated that SchB mediated alleviation of CsA induced nephrotoxicity by preventing the accumulation of ROS by way of suppressing oxidative stress, apoptosis and autophagy.

A combined approach to early detect in vitro drug-induced hemostatic changes in preclinical safety.

Early detection of drug-induced alterations of hemostasis is challenging. Drugs can affect different components of the Virchow's triad and measurement of plasmatic coagulation times lacks sensitivity. New techniques for a more global assessment of the hemostasis are now available: the impedance platelet aggregometry, the thromboelastography and the thrombin generation measurement. The aim of this study was to evaluate three techniques (i.e.: Multiplate®, TEG® and CAT) for the in vitro detection of the effect of a drug known to induce hemostatic alterations in a preclinical safety environment. Cyclosporine A was chosen and tested at 4 concentrations after solubilization in DMSO in Wistar rats and Beagle dogs. The results obtained were comparable between both species except for the thrombin generation in platelet rich plasma. Enhanced platelet aggregability was observed after ADP stimulation and alterations of the thromboelastograms consisted in decreased maximum amplitude and increased LY30. A dual effect on thrombin generation was observed and suggested that CsA may interact with platelets in rat platelet rich plasma and speed up thrombin generation. The results of this study indicate that using a combined approach on hemostasis testing in preclinical safety it is possible to detect in vitro drug-induced alterations of hemostasis.

Pharmacokinetic and nephroprotective benefits of using Schisandra chinensis extracts in a cyclosporine A-based immune-suppressive regime.

Cyclosporine A (CsA) is a powerful immunosuppressive drug. However, nephrotoxicity resulting from its long-term usage has hampered its prolonged therapeutic usage. Schisandra chinensis extracts (SCE) have previously been used in traditional Chinese medicine and more recently coadministered with Western medicine for the treatment of CsA-induced side effects in the People's Republic of China. This study aimed to investigate the possible effects of SCE on the pharmacokinetics of CsA in rats and elucidate the potential mechanisms by which it hinders the development of CsA-induced nephrotoxicity. A liquid chromatography/tandem mass spectrometry method was developed and validated for determining the effect of SCE on the pharmacokinetics of CsA. Male Sprague Dawley rats, which were administered with CsA (25 mg/kg/d) alone or in combination with SCE (54 mg/kg/d and 108 mg/kg/d) for 28 days, were used to evaluate the nephroprotective effects of SCE. Our study showed that SCE increased the mean blood concentration of CsA. Furthermore, we found that the concomitant administration of SCE alongside CsA prevented the disruption of catalase activity and reduction in creatinine, urea, renal malondialdehyde, and glutathione peroxidase levels that would have otherwise occurred in the absence of SCE administration. SCE treatment markedly suppressed the expression of 4-hydroxynonenal, Bcl-2-associated X protein, cleaved caspase 3, and autophagy-related protein LC3 A/B. On the other hand, the expression of heme oxygenase-1, nuclear factor erythroid 2-related factor 2 (Nrf2), and P-glycoprotein was enhanced by the very same addition of SCE. SCE was also able to increase the systemic exposure of CsA in rats. The renoprotective effects of SCE were thought to be mediated by its antiapoptotic and antioxidant abilities, which caused the attenuation of CsA-induced autophagic cell death. All in all, these findings suggest the prospective use of SCE as an effective adjunct in a CsA-based immunosuppressive regimen.

The effects of cyclosporin A and Heteropterys tomentosa on the rat liver.

Cyclosporin A (CsA) is a widely employed immunosuppressive drug that is associated with several side effects, among then hepatotoxicity. Heteropterys tomentosa is a Brazilian plant efficient in reducing damage caused by CsA on the rat testis and prostate. The aim of this study was to evaluate the effect of CsA and H. tomentosa (administered isolated or simultaneously) on the liver of Wistar rats. The animals were treated daily with water (control), CsA (15 mg/kg/day), H. tomentosa infusion or CsA+H. tomentosa, for 21 or 56 days. The treatments did not alter liver morphology or cause fibrosis. H. tomentosa administered for 21 days increased the number of hepatocyte nuclei and Kupffer cell volumetric proportion. After 56 days of treatment, H. tomentosa administration did not alter the parameters analyzed. Biochemical plasma dosages and liver stereology showed impairment caused by CsA-treatment after 21 days; these results were not observed after 56 days of treatment. The simultaneous treatment with CsA and H. tomentosa for 21 or 56 days did not alleviate nor accentuate CsA hepatic effects. The present study showed that the 21 days treatment with CsA caused more alteration to the liver than the 56 days treatment; this could be related to hepatic recovery after the long term treatment.

Exploring the zebrafish embryo as an alternative model for the evaluation of liver toxicity by histopathology and expression profiling.

The whole zebrafish embryo model (ZFE) has proven its applicability in developmental toxicity testing. Since functional hepatocytes are already present from 36 h post fertilization onwards, whole ZFE have been proposed as an attractive alternative to mammalian in vivo models in hepatotoxicity testing. The goal of the present study is to further underpin the applicability of whole ZFE for hepatotoxicity testing by combining histopathology and next-generation sequencing-based gene expression profiling. To this aim, whole ZFE and adult zebrafish were exposed to a set of hepatotoxic reference compounds. Histopathology revealed compound and life-stage-specific effects indicative of toxic injury in livers of whole ZFE and adult zebrafish. Next-generation sequencing (NGS) was used to compare transcript profiles in pooled individual RNA samples of whole ZFE and livers of adult zebrafish. This revealed that hepatotoxicity-associated expression can be detected beyond the overall transcription noise in the whole embryo. In situ hybridization verified liver specificity of selected highly expressed markers in whole ZFE. Finally, cyclosporine A (CsA) was used as an illustrative case to support applicability of ZFE in hepatotoxicity testing by comparing CsA-induced gene expression between ZFE, in vivo mouse liver and HepaRG cells on the levels of single genes, pathways and transcription factors. While there was no clear overlap on single gene level between the whole ZFE and in vivo mouse liver, strong similarities were observed between whole ZFE and in vivo mouse liver in regulated pathways related to hepatotoxicity, as well as in relevant overrepresented transcription factors. In conclusion, both the use of NGS of pooled RNA extracts analysis combined with histopathology and traditional microarray in single case showed the potential to detect liver-related genes and processes within the transcriptome of a whole zebrafish embryo. This supports the applicability of the whole ZFE model for compound-induced hepatotoxicity screening.

The protective effects of omega 3 fatty acids and sesame oil against cyclosporine A-induced nephrotoxicity.

Cyclosporine A (CsA) is a drug used in autoimmune disorders and organ transplantations. Omega 3 fatty acids (O-3) and sesame oil (SO) have antioxidant properties. We aimed to investigate and compare the protective effects of O-3 and SO against CsA-induced nephrotoxicity. Seven groups of male Wistar albino rats were included in the study. In group 1 (control), saline was administered, and in group 2, CsA (subcutaneously) was administered. In group 3, CsA+SO (orally; p.o.) was given; in group 4, CsA+O-3 (p.o.) was given; and in group 5, CsA+SO+O-3 was given. In group 6, SO was administered, and in group 7, O-3 was administered. After 15 days of treatment, kidneys were excised. Histopathological evaluation, apoptotic cell count, and renal/hepatic function tests were performed. In group 2, vacuolar degeneration and necrosis of tubular cells as well as hemorrhagic foci were observed; the apoptotic cell number was higher than in the control (P < 0.001). In groups 3, 4, and 5, tubular scores and apoptotic cell count were lower than in group 2 (P < 0.01 and P < 0.001, respectively). In groups 6 and 7, healthy renal histology and a few apoptotic cells were determined. In groups 2, 3, 4, and 5, blood urea nitrogen was higher and albumin was lower than in the control (P < 0.001). Liver enzymes were unchanged. O-3/SO showed similar protective effects against CsA-induced nephrotoxicity, as revealed by a remarkable decrease in histopathological changes and apoptotic cell count. However, impaired renal function tests were not improved with O-3/SO treatment. SO and O-3 can be used as chemoprotectants against CsA.

Safety evaluation of nanoliposomes containing cyclosporine a after ocular administration.

AIM: Cyclosporine A (CyA) is an anti inflammatory drug which modulates immune system. We prepared two liposomal formulations of CyA for ophthalmic administration. In the present study, the safety of these formulations was tested in rabbits. MATERIALS AND METHODS: Fusogenic and positively charged liposomes were prepared by solvent evaporation method. CyA concentration in ophthalmic preparations was 0.2% w/v. Twenty New Zealand albino rabbits (40 eyes) were divided into two groups. Right eyes were treated and left eyes served as control. Eyes were examined clinically in 1, 3, 7, 14 and 28th days of the study. Eleven eyes were enucleated for pathological evaluation at the end of the study. RESULTS: Mean size and charge of positively charged and fusogenic liposomes were 110.7 ± 1.5 and 114.9 ± 15.2 nm; 19.0 ± 2.2 and 2.5 ± 0.5 mV, respectively. Clinically, there were transient conjunctival injections and corneal epithelial defects in a few cases which were not limited to the treated eyes. Positively charged liposomes caused conjunctival injection in two cases, while this complication occurred in only one eye after administration of fusogenic liposomes. Histopathological examination revealed the presence of follicular conjunctivitis in two eyes with conjunctival injection. Inflammation in cases received the fusogenic form of the drug was mild and non-specific. CONCLUSIONS: The results of this study suggest that fusogenic liposomal preparation of CyA is safe and can be useful for future studies.

Antiapoptotic and antioxidant effects of GSPE in preventing cyclosporine A-induced cardiotoxicity.

OBJECTIVES: Cyclosporine A (CsA) is an immunosuppressive drug, but cardiotoxicity is one of its side effects. Free oxygen radical damage and apoptosis are considered to be responsible for CsA-induced cardiotoxicity. Grape seed proanthocyanidin extract (GSPE) displays antioxidant and antiapoptotic activities. Therefore, we aimed to evaluate the effect of GSPE on CsA-induced cardiotoxicity. MATERIALS AND METHODS: Twenty-four rats were divided into four groups, with six rats in each group. CsA-induced nephropathy was induced by administration of 25 mg/kg CsA. The experiment was discontinued on day 21, and total oxidant system (TOS), total antioxidant system (TAS), oxidative stress index (OSI), and malondialdehyde (MDA) were measured in order to evaluate oxidative damage to the heart tissue. In addition to cardiac histopathology, transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) was performed to determine apoptosis. RESULTS: The CsA group showed a significant increase in TOS, OSI, MDA, cardiac histopathological score, and apoptotic index (AI); in the CsA + GSPE group, OSI, MDA, cardiac histopathological score, and AI decreased significantly, and TAS levels showed a significant increase. CONCLUSION: In this study, we demonstrated for the first time in the literature that GSPE prevents CsA cardiotoxicity and that this effect can be achieved by antiapoptotic and antioxidant activities.

Renoprotective effects of green tea extract on renin-angiotensin-aldosterone system in chronic cyclosporine-treated rats.

BACKGROUND: Renin-angiotensin-aldosterone system (RAAS) activation plays an important role in cyclosporine (CsA)-induced nephropathy. The main aim of this study was to test whether the administration of green tea extract (GTE) prevents the development of CsA-induced nephrotoxicity. METHODS: The rats were treated for 21 days and divided into four groups (n = 6/group): control group (0.9% saline injection), CsA group (30 mg/kg/day by intraperitoneal injection), CsA-GTE group (CsA plus GTE 100 mg/kg/day subcutaneous injection) and GTE group (GTE alone). RESULTS: There were significant increased levels of serum blood urea nitrogen and creatinine in the CsA group compared with that of the control group and significantly improved in the CsA-GTE group. Biochemical analysis showed that the plasma renin activity (PRA) and serum concentration of aldosterone were significantly increased in the CsA group compared with the control group and significantly decreased in the CsA-GTE group compared with the CsA group. The total level of renin protein expression was significantly higher in the CsA group than in the control group, and it was lower in the CsA-GTE group than in the CsA group. CONCLUSIONS: CsA treatment increases the PRA and intrarenal renin levels and induces nephrotoxicity. The protective effects of GTE on CsA-induced structural and functional alternations of the kidney may be the blockage of RAAS.

Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies.

Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring kidney dysfunction in humans. The transmembrane tubular protein kidney injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of kidney injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.

Eficacia y seguridad a corto plazo de etanercept en la psoriasis / Short term efficacy and safety of etanercept in psoriasis

La psoriasis es una enfermedad crónica, que cursa por brotes, y que en un momento determinado de su evolución, o en ciertos pacientes, puede afectar una gran parte de la superficie corporal con graves repercusiones físicas y psíquicas. Los tratamientos utilizados en este tipo de pacientes se asocian a múltiples efectos secundarios y requieren numerosos controles clínicos y analíticos. La aparición de las nuevas terapias biológicas en el arsenal terapéutico del dermatólogo ha aportado numerosas ventajas para el control y mantenimiento del paciente psoriásico. La facilidad de uso, limpieza, comodidad posológica y sencillez de su manejo han cambiado la perspectiva de la enfermedad. Su eficacia parece comparable o superior a la conseguida por terapias sistémicas clásicas como la fototerapia, los retinoides, metotrexato o ciclosporina. Presentamos un caso clínico de psoriasis grave, que presentó una rápida y completa respuesta a etanercept. A propósito del mismo realizamos un revisión bibliográfica dirigida a los aspectos de seguridad y eficacia a corto plazo –menos de 12 semanas de tratamiento– en pacientes psoriásicos tratados con esta molécula (AU)

Psoriasis is a chronic disease that occurs in episodes and which, in a certain moment of its evolution or in some patients, may affect a large portion of the body surface with serious physical and psychological repercussions. The treatment used in this type of patient is associated to many side effects and requires numerous clinical and laboratory controls. We present a clinical case of severe psoriasis that presented a rapid and complete response to etanercept. Based on this case, we performed a bibliographic review aimed at the short-term safety and efficacy aspects, less than 12 weeks of treatment, in psoriatic patients treated with this molecule (AU)

Effects of tomato extract on oxidative stress induced toxicity in different organs of rats.

Tomato products containing lycopene are believed to be associated with decreased risk of chronic diseases including cancer, and its effects are suggested to be due to antioxidant effect of lycopene. The aim of this research was to study the effects of tomato extract on acetaminophen (APAP), amiodarone (ADN) and cyclosporine A (CsA)-induced liver, lung and kidney toxicity, respectively. Previous studies have shown that free radical reactions may play important roles in toxicity of these drugs. Rats received a single dose of APAP (750mg/kg, i.p.) before treatment with tomato extract (5mg/kg, oral) for seven consecutive days, ADN (100mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 10 consecutive days, or CsA (250mg/kg, i.p.) plus tomato extract (5mg/kg, oral) for 14 consecutive days. At the end of each treatment, the animals were sacrificed and the related organ tissues were collected for biochemical and histopathological examinations. Simultaneous treatment of tomato extract ameliorated tissue damage, biochemical indices, and oxidative stress parameters against APAP-induced acute hepatotoxicity, but had less beneficial effects on ADN-induced lung toxicity and little effect against CsA-induced nephrotoxicity. Therefore, tomato products may be beneficial for the prevention and therapy of toxicity induced by ADN and APAP.

Effect of ellagic acid on cyclosporine A-induced oxidative damage in the liver of rats.

Cyclosporine A (CsA) is an immunosuppressor, which is most frequently used in the transplant surgery and in the treatment of autoimmune diseases. It has been shown that CsA is able to generate reactive oxygen species and lipid peroxidation, which are directly involved in the CsA nephrotoxicity, hepatotoxicity and cardiotoxicity. This study was undertaken to investigate the protective effect of ellagic acid (EA), a polyphenolic compound against CsA-induced liver injury in male Wistar rats. In this study, CsA was administered orally (25 mg/kg body weight) for 21 days to induce toxicity. EA was administered orally (12.5, 25 and 50 mg/kg body weight) for 21 days along with oral administration of CsA. CsA-induced liver damage was evidenced by increased activities of serum hepatic enzymes namely aspartate transaminase, alanine transaminase, alkaline phosphatase and lactate dehydrogenase with a significant elevation of lipid peroxidation markers such as thiobarbituric acid reactive substances (TBARS) and hydroperoxides in the liver. The levels of enzymic antioxidants such as superoxide dismutase, catalase and glutathione-S-transferase and non-enzymic antioxidants (vitamin C, vitamin E and reduced glutathione) were also decreased in CsA-treated rats. Administrations of EA at 50 mg/kg body weight significantly decreased the activities of hepatic marker enzymes compared with other doses of EA (12.5, 25 mg/kg body weight). In addition, the levels of TBARS and hydroperoxides were significantly decreased and the levels of enzymic and non-enzymic antioxidants significant increased on treatment with EA in the liver. The biochemical observation was supplemented by histopathologic examination of liver section. The results of this study indicate that EA might play an important role in protecting CsA-induced oxidative damage in the liver.

Heteropterys aphrodisiaca infusion reduces the collateral effects of cyclosporine A on the testis.

Cyclosporine A (CsA) is known to have testicular toxicity, leading to male infertility. Stimulant and aphrodisiac properties have been attributed to the plant, Heteropterys aphrodisiaca. Thus, the present work was undertaken to evaluate the association of the drug and the medicinal herb in Wistar rats, applying testicular morphometry and ultrastructure. Twenty-four rats were used, divided into four groups: I, control; II, CsA; III, simultaneous use of CsA and H. aphrodisiaca; IV, H. aphrodisiaca. Daily administration by gavage was carried out, during 56 days, of water (sham), CsA in a dose of 15 mg/kg per day and/or H. aphrodisiaca in a dose of 0.5 ml of the infusion prepared with 25 g of roots/100 ml of boiling water. Increased body weight was observed for all groups, but the animals that received only CsA showed the smallest body weight gain. Morphometry showed increased connective tissue volumetric proportion and decreased Leydig cell volumetric proportion in CsA-treated rats. Using transmission electron microscopy, it was possible to ascertain that CsA caused seminiferous epithelium degeneration, resulting in Sertoli cell vacuolization, abnormal round and elongated spermatids and large accumulation of residual cytoplasm at the epithelium border next to the lumen. Expanded intercellular spaces between germ cells were still observed in H. aphrodisiaca-treated rat testes. The administration of H. aphrodisiaca infusion to CsA-treated rats diminished nearly all the CsA-induced damage to the testis ultrastructure, suggesting that H. aphrodisiaca infusion may be used combined with CsA to reduce CsA-induced injuries in the testis.