Secondary Adverse Effects Research Articles

Angelicin inhibits liver cancer growth invitro and invivo.

Previous studies have reported that angelicin exerted antiproliferative effects on several types of tumor cell. However, to the best of our knowledge, the effects of angelicin monotherapy on human liver cancer remain to be investigated. In the present study, the antitumor activity of angelicin was evaluated in vitro and in vivo, and the molecular mechanisms underlying its effects were investigated. The present results revealed that angelicin induced apoptosis in liver cancer cells in a dose- and time-dependent manner. Furthermore, in HepG2 and Huh-7 cells, angelicin-induced apoptosis was demonstrated to be mitochondria dependent, involving the phosphatidylinositol-4,5-bisphosphate 3-kinase/RAC-α serine/threonine-protein kinase signaling pathway. In addition, administration of angelicin to mice bearing liver tumor xenografts inhibited tumor growth, without producing significant secondary adverse effects. These results suggested that angelicin may have potential as a novel therapeutic agent for the treatment of patients with liver cancer.

Carbon Nanotubes Disrupt Iron Homeostasis and Induce Anemia of Inflammation through Inflammatory Pathway as a Secondary Effect Distant to Their Portal-of-Entry.

Although numerous toxicological studies have been performed on carbon nanotubes (CNTs), a few studies have investigated their secondary and indirect effects beyond the primary target tissues/organs. Here, a cascade of events are investigated: the initiating event and the subsequent key events necessary for the development of phenotypes, namely CNT-induced pro-inflammatory effects on iron homeostasis and red blood cell formation, which are linked to anemia of inflammation (AI). A panel of CNTs are prepared including pristine multiwall CNTs (P-MWCNTs), aminated MWCNTs (MWCNTs-NH2 ), polyethylene glycol MWCNTs (MWCNTs-PEG), polyethyleneimine MWCNTs (MWCNTs-PEI), and carboxylated MWCNTs (MWCNTs-COOH). It has been demonstrated that all CNT materials provoke inflammatory cytokine interleukin-6 (IL-6) production and stimulate hepcidin induction, associated with disordered iron homeostasis, irrespective of exposure routes including intratracheal, intravenous, and intraperitoneal administration. Meanwhile, PEG and COOH modifications can ameliorate the activation of IL-6-hepcidin signaling. Long-term exposure of MWCNTs results in AI and extramedullary erythropoiesis. Thus, an adverse outcome pathway is identified: MWCNT exposure leads to inflammation, hepatic hepcidin induction, and disordered iron metabolism. Together, the combined data depict the hazardous secondary toxicity of CNTs in incurring anemia through inflammatory pathway. This study will also open a new avenue for future investigations on CNT-induced indirect and secondary adverse effects.

Lissoclibadin 1, a Polysulfur Aromatic Alkaloid from the Indonesian Ascidian Lissoclinum cf. badium, Induces Caspase-Dependent Apoptosis in Human Colon Cancer Cells and Suppresses Tumor Growth in Nude Mice.

Lissoclibadins, polysulfur aromatic alkaloids, were isolated from the Indonesian ascidian Lissoclinum cf. badium. Lissoclibadins 1 (1), 3 (2), 4 (3), 7 (4), 8 (5), and 14 (6) inhibited the growth of four human solid cancer cell lines: HCT-15 (colon adenocarcinoma), HeLa-S3 (cervix adenocarcinoma), MCF-7 (breast adenocarcinoma), and NCI-H28 (mesothelioma). Lissoclibadin 1 (1) exerted the most potent cytotoxic effects in vitro and mainly promoted apoptosis through an intrinsic pathway with the activation of a caspase-dependent pathway in HCT-15 cells. In vivo studies demonstrated that 1 suppressed tumor growth in nude mice carrying HCT-15 cells without significant secondary adverse effects. In conclusion, the results obtained in the present study demonstrate that 1 has potential as a chemotherapeutic candidate for preclinical investigations.

Peperomin E reactivates silenced tumor suppressor genes in lung cancer cells by inhibition of DNA methyltransferase.

Advanced lung cancer has poor prognosis owing to its low sensitivity to current chemotherapy agents. Therefore, discovery of new therapeutic agents is urgently needed. In this study, we investigated the antitumor effects of peperomin E, a secolignan isolated from Peperomia dindygulensis, a frequently used Chinese folk medicine for lung cancer treatment. The results indicate that peperomin E has antiproliferative effects, promoting apoptosis and cell cycle arrest in non‐small‐cell lung cancer (NSCLC) cell lines in a dose‐dependent manner, while showing lower toxicity against normal human lung epidermal cells. Peperomin E inhibited tumor growth in A549 xenograft BALB/c nude mice without significant secondary adverse effects, indicating that it may be safely used to treat NSCLC. Furthermore, the mechanisms underlying the anticancer effects of peperomin E have been investigated. Using an in silico target fishing method, we observed that peperomin E directly interacts with the active domain of DNA methyltransferase 1 (DNMT1), potentially affecting its genome methylation activity. Subsequent experiments verified that peperomin E decreased DNMT1 activity and expression, thereby decreasing global methylation and reactivating the epigenetically silenced tumor suppressor genes including RASSF1A,APC,RUNX3, and p16INK4, which in turn activates their mediated pro‐apoptotic and cell cycle regulatory signaling pathways in lung cancer cells. The observations herein report for the first time that peperomin E is a potential chemotherapeutic agent for NSCLC. The anticancer effects of peperomin E may be partly attributable to its ability to demethylate and reactivate methylation‐silenced tumor suppressor genes through direct inhibition of the activity and expression of DNMT1.

Pharmacological and neuroethological study of the acute and chronic effects of lamotrigine in the genetic audiogenic seizure hamster (GASH:Sal).

The present study aimed to investigate the behavioral and anticonvulsant effects of lamotrigine (LTG) on the genetic audiogenic seizure hamster (GASH:Sal), an animal model of audiogenic seizure that is in the validation process. To evaluate the efficiency of acute and chronic treatments with LTG, GASH:Sals were treated with LTG either acutely via intraperitoneal injection (5-20mg/kg) or chronically via oral administration (20-25mg/kg/day). Their behavior was assessed via neuroethological analysis, and the anticonvulsant effect of LTG was evaluated based on the appearance and the severity of seizures. The results showed that acute administration of LTG exerts an anticonvulsant effect at the lowest dose tested (5mg/kg) and that chronic oral LTG treatment exerts an anticonvulsant effect at a dose of 20-25mg/kg/day. Furthermore, LTG treatment induced a low rate of secondary adverse effects. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Ailanthone Inhibits Huh7 Cancer Cell Growth via Cell Cycle Arrest and Apoptosis In Vitro and In Vivo

While searching for natural anti-hepatocellular carcinoma (HCC) components in Ailanthus altissima, we discovered that ailanthone had potent antineoplastic activity against HCC. However, the molecular mechanisms underlying the antitumor effect of ailanthone on HCC have not been examined. In this study, the antitumor activity and the underlying mechanisms of ailanthone were evaluated in vitro and in vivo. Mechanistic studies showed that ailanthone induced G0/G1-phase cell cycle arrest, as indicated by decreased expression of cyclins and CDKs and increased expression of p21 and p27. Our results demonstrated that ailanthone triggered DNA damage characterized by activation of the ATM/ATR pathway. Moreover, ailanthone-induced cell death was associated with apoptosis, as evidenced by an increased ratio of cells in the subG1 phase and by PARP cleavage and caspase activation. Ailanthone-induced apoptosis was mitochondrion-mediated and involved the PI3K/AKT signaling pathway in Huh7 cells. In vivo studies demonstrated that ailanthone inhibited the growth and angiogenesis of tumor xenografts without significant secondary adverse effects, indicating its safety for treating HCC. In conclusion, our study is the first to report the efficacy of ailanthone against Huh7 cells and to elucidate its underlying molecular mechanisms. These findings suggest that ailanthone is a potential agent for the treatment of liver cancer.

Xerophilusin B induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma cells and does not cause toxicity in nude mice.

Esophageal cancer is the eighth most common cancer in the world and ranks as the sixth leading cause of cancer-related mortality. Esophageal cancer has a poor prognosis partially due to its low sensitivity to chemotherapy agents, and the development of new therapeutic agents is urgently needed. Here, the antitumor activity of a natural ent-kaurane diterpenoid, xerophilusin B (1), which was isolated from Isodon xerophilus, a perennial herb frequently used in Chinese folk medicine for tumor treatment, was investigated. Compound 1 exhibited antiproliferative effects against esophageal squamous cell carcinoma (ESCC) cell lines in a time- and dose-dependent manner with lower toxicity against normal human and murine cell lines. In vivo studies demonstrated that 1 inhibited tumor growth of a human esophageal tumor xenograft in BALB/c nude mice without significant secondary adverse effects, indicating its safety in treating ESCC. Furthermore, 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines. In conclusion, the observations herein reported showed that 1 is a potential chemotherapeutic agent for ESCC and merits further preclinical and clinical investigation for cancer drug development.

A Comparative Study between Hyaluronic Acid and Corticosteroids for the Treatment of the Greater Trochanteric Pain Syndrome

Objective: To date, there are no studies addressing the efficacy of hyaluronic acid (HA) injections at the trochanteric bursa in patients with greater trochanteric pain syndrome (GTPS). The objective of the study was to compare the efficacy and safety of HA to corticosteroid injections for the treatment of the GTPS. Methods: This prospective, randomized, two-arm trial involved 47 patients with unilateral or bilateral GTPS. Patients received an intra-bursal injection of 40 mg triamcinolone acetonide plus 1mL lidocaine, or of 60 mg HA. Patients completed visual analog scales (VAS) and Likert scales to evaluate interference of pain with daily activity, recovery from pain, and treatment satisfaction. A non-inferiority analysis was also performed. Results: Mean VAS score for pain significantly decreased comparing baseline with 1, 3 and 6 months in both treatment groups. VAS score for pain on palpation was also significantly lower than baseline in both arms. No significant differences were found between groups. Analysis of Likert scales at the sixth month didn’t detect statistically significant differences between treatment groups. The non-inferiority analysis showed that the treatment with HA was non-inferior to corticosteroids. No secondary adverse effects were found among the patients of both groups during the follow-up. Conclusions: The treatment with HA has demonstrated to be non-inferior to corticosteroids after 6 months of follow-up in patients with GTPS. Therefore, the treatment with HA may be considered an effective alternative therapeutic strategy to reduce pain in patients in whom the treatment with corticosteroids, or other therapies, have been unsuccessful or contraindicated.

Clinical use of deslorelin (GnRH agonist) in companion animals: a review.

Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin®, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets.

Clinical challenges in the management of isolated GH deficiency type IA in adulthood

SummaryIsolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet.Learning points Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.

From Gene Engineering to Gene Modulation and Manipulation: Can We Prevent or Detect Gene Doping in Sports?

During the last 2 decades, progress in deciphering the human gene map as well as the discovery of specific defective genes encoding particular proteins in some serious human diseases have resulted in attempts to treat sick patients with gene therapy. There has been considerable focus on human recombinant proteins which were gene-engineered and produced in vitro (insulin, growth hormone, insulin-like growth factor-1, erythropoietin). Unfortunately, these substances and methods also became improper tools for unscrupulous athletes. Biomedical research has focused on the possible direct insertion of gene material into the body, in order to replace some defective genes in vivo and/or to promote long-lasting endogenous synthesis of deficient proteins. Theoretically, diabetes, anaemia, muscular dystrophies, immune deficiency, cardiovascular diseases and numerous other illnesses could benefit from such innovative biomedical research, though much work remains to be done. Considering recent findings linking specific genotypes and physical performance, it is tempting to submit the young athletic population to genetic screening or, alternatively, to artificial gene expression modulation. Much research is already being conducted in order to achieve a safe transfer of genetic material to humans. This is of critical importance since uncontrolled production of the specifically coded protein, with serious secondary adverse effects (polycythaemia, acute cardiovascular problems, cancer, etc.), could occur. Other unpredictable reactions (immunogenicity of vectors or DNA-vector complex, autoimmune anaemia, production of wild genetic material) also remain possible at the individual level. Some new substances (myostatin blockers or anti-myostatin antibodies), although not gene material, might represent a useful and well-tolerated treatment to prevent progression of muscular dystrophies. Similarly, other molecules, in the roles of gene or metabolic activators [5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), GW1516], might concomitantly improve endurance exercise capacity in ischaemic conditions but also in normal conditions. Undoubtedly, some athletes will attempt to take advantage of these new molecules to increase strength or endurance. Antidoping laboratories are improving detection methods. These are based both on direct identification of new substances or their metabolites and on indirect evaluation of changes in gene, protein or metabolite patterns (genomics, proteomics or metabolomics).

From too much and too little towards stratified psychiatry and pathophysiology

As J. Rapoport points out in her incisive commentary, pediatric psychopharmacology stands now at the crossroads of both too much and too little. Certainly, the number of options now available to clinicians far exceeds the resources physicians could draw on even two decades ago. However, appreciation of this apparent cornucopia is tempered by awareness of how limited therapeutic benefits tend to be when examined in controlled studies and by increasing insight into the numerous secondary adverse effects that inevitably accrue. Too little benefit, too many adverse effects.

Late effects of orbital enucleation and radiation on maxillofacial prosthetic rehabilitation: A clinical report

The retinoblastoma is one of the most common tumors of the eye diagnosed in childhood. The treatment for patients with retinoblastoma includes surgical removal of the lesion along with adjunctive chemotherapy and radiotherapy. If the tumor is controlled, these treatments can have secondary adverse effects pertaining to the growth and development of orofacial structures in young patients. This clinical report describes the prosthetic rehabilitation of a patient who underwent enucleation followed by radiation therapy and adjunctive chemotherapy to treat the primary diagnosis of retinoblastoma. This therapy resulted in a combination of dental and facial growth and developmental abnormalities.

Prostate Cancer Diagnosis Among Men With Isolated High-Grade Intraepithelial Neoplasia Enrolled Onto a 3-Year Prospective Phase III Clinical Trial of Oral Toremifene

Prostate cancer (PCa) prevention remains an appealing strategy for the reduction of overtreatment and secondary adverse effects. We evaluated the efficacy of toremifene citrate 20 mg in PCa prevention among men with isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on biopsy. One thousand five hundred ninety men with HGPIN, or HGPIN and atypia, and no PCa on prostate biopsy were randomly assigned 1:1 to receive toremifene citrate 20 mg or placebo in a 3-year phase III, double-blind, multicenter trial. Men underwent annual biopsy until cancer detection or study end. Efficacy analysis was performed in 1,467 men who underwent at least one on-study biopsy. Baseline risk factors were evaluated to determine influence on cancer detection. Cancer was detected in 34.7% and 32.3% of men in the placebo and treatment groups, respectively, with no observed difference (P = .39, log-rank test) in PCa-free survival. The 3-year Kaplan-Meier PCa-free survival estimate was 54.9% (99% CI, 43.3% to 66.5%) in the placebo group and 59.5% (99% CI, 48.1% to 70.9%) in the treatment group. Exploration of baseline risk factors demonstrated no subset in which a risk reduction was observed. In the placebo group, 17.9%, 12.9%, and 13.6% of men at risk at the beginning of years 1, 2, and 3, respectively, were diagnosed with PCa. Although toremifene 20 mg did not lower the PCa detection rate, men with isolated HGPIN have a high likelihood of eventual PCa diagnosis, demonstrating they are ideal candidates for inclusion in chemoprevention trials and require surveillance by periodic prostate biopsy.

Eriocalyxin B induces apoptosis and cell cycle arrest in pancreatic adenocarcinoma cells through caspase- and p53-dependent pathways

Pancreatic cancer is difficult to detect early and responds poorly to chemotherapy. A breakthrough in the development of new therapeutic agents is urgently needed. Eriocalyxin B (EriB), isolated from the Isodon eriocalyx plant, is an ent-kaurane diterpenoid with promise as a broad-spectrum anti-cancer agent. The anti-leukemic activity of EriB, including the underlying mechanisms involved, has been particularly well documented. In this study, we demonstrated for the first time EriB's potent cytotoxicity against four pancreatic adenocarcinoma cell lines, namely PANC-1, SW1990, CAPAN-1, and CAPAN-2. The effects were comparable to that of the chemotherapeutic camptothecin (CAM), but with much lower toxicity against normal human liver WRL68 cells. EriB's cytoxicity against CAPAN-2 cells was found to involve caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Moreover, the p53 pathway was found to be activated by EriB in these cells. Furthermore, in vivo studies showed that EriB inhibited the growth of human pancreatic tumor xenografts in BALB/c nude mice without significant secondary adverse effects. These results suggest that EriB should be considered a candidate for pancreatic cancer treatment.

Effect of vertebroplasty on pain relief, quality of life, and the incidence of new vertebral fractures: A 12-month randomized follow-up, controlled trial

Uncertainty regarding the benefits of vertebroplasty (VP) for the treatment of acute osteoporotic vertebral fractures has recently arisen. A prospective, controlled, randomized single-center trial (ClinicalTrials.gov registration number NCT00994032) was designed to compare the effects of VP versus conservative treatment on the quality of life and pain in patients with painful osteoporotic vertebral fractures, new fractures and secondary adverse effects were also analyzed during a 12-month follow-up period. A total of 125 patients were randomly assigned to receive conservative treatment or VP. The primary end point was to compare the evolution of the quality of life (Quality of Life Questionnaire of the European Foundation for Osteoporosis [Qualeffo-41] and pain (Visual Analogue Scale [VAS]) during a 12 month follow-up. Secondary outcomes included comparison of analgesic consumption, clinical complications, and radiological vertebral fractures at the same time points. Both arms showed significant improvement in VAS scores at all time points, with greater improvement (p = 0.035) in the VP group at the 2-month follow-up. Significant improvement in Qualeffo total score was seen in the VP group throughout the study, whereas this was not seen in the conservative treatment arm until the 6-month follow-up. VP treatment was associated with a significantly increased incidence of vertebral fractures (odds ratio [OR], 2 · 78; 95% confidence interval [CI], 1.02-7.62, p = 0.0462). VP and conservative treatment are both associated with significant improvement in pain and quality of life in patients with painful osteoporotic vertebral fractures over a 1-year follow-up period. VP achieved faster pain relief with significant improvement in the pain score at the 2-month follow-up but was associated with a higher incidence in vertebral fractures.

Estudio comparativo del perfil cognitivo de niños en edad escolar con tumores cerebrales infratemporales y supratentoriales que finalizaron el tratamiento médico. Impacto en el funcionamiento escolar y social de la calidad de vida relacionada con salud

Introduction: Due to scientific advances, there is a growing number of pediatric patients surviving cancer. In general, for children who suffer from central nervous system tumors, this survival is associated with secondary adverse effects, such as cognitive deficits. Objetive: To assess cognitive functions and quality of life in children with infratentorial and supratentorial brain tumors. Methods: An analytical observational and prospective study was conducted. The total sample consisted of 51 subjects. The following measurement instruments were used: Wechsler Intelligence Scale for Children, Fourth Edition (WISC IV), Cognitive Assessment System (CAS), Test of Memory and Learning (TOMAL), Graffar Scale; and Peds Quality of Life 4.0 Results: The comparison of the results did not show significant differences between infratentorial and supratentorial tumor location. All patients that were evaluated in the post-cancer-treatment period reveled a similar significant impairment in all the areas studied compared with the level expected in the general population. The most severely affected cognitive functions were processing speed and attention span, mainly on the planning tasks. The findings also show that quality of life at school is severely affected in these children. Conclusions: This is a preliminary study whose results may define a general trend of neurocognitive status, analyzing its impact on quality of life of the study population an posing useful questions for future research.

Keratinocyte-Targeted Overexpression of the Glucocorticoid Receptor Delays Cutaneous Wound Healing

Delayed wound healing is one of the most common secondary adverse effects associated to the therapeutic use of glucocorticoid (GC) analogs, which act through the ligand-dependent transcription factor GC-receptor (GR). GR function is exerted through DNA-binding-dependent and –independent mechanisms, classically referred to as transactivation (TA) and transrepression (TR). Currently both TA and TR are thought to contribute to the therapeutical effects mediated by GR; however their relative contribution to unwanted side effects such as delayed wound healing is unknown. We evaluated skin wound healing in transgenic mice with keratinocyte-restricted expression of either wild type GR or a mutant GR that is TA-defective but efficient in TR (K5-GR and K5-GR-TR mice, respectively). Our data show that at days (d) 4 and 8 following wounding, healing in K5-GR mice was delayed relative to WT, with reduced recruitment of granulocytes and macrophages and diminished TNF-α and IL-1β expression. TGF-β1 and Kgf expression was repressed in K5-GR skin whereas TGF-β3 was up-regulated. The re-epithelialization rate was reduced in K5-GR relative to WT, as was formation of granulation tissue. In contrast, K5-GR-TR mice showed delays in healing at d4 but re-established the skin breach at d8 concomitant with decreased repression of pro-inflammatory cytokines and growth factors relative to K5-GR mice. Keratinocytes from both transgenic mice closed in vitro wounds slower relative to WT, consistent with the in vivo defects in cell migration. Overall, the delay in the early stages of wound healing in both transgenic models is similar to that elicited by systemic treatment with dexamethasone. Wound responses in the transgenic keratinocytes correlated with reduced ERK activity both in vivo and in vitro. We conclude that the TR function of GR is sufficient for negatively regulating early stages of wound closure, while TA by GR is required for delaying later stages of healing.

P.3.d.005 Treatment of acute olanzapine-induced glucose dysregulation in rats: oral administration of metformin, rosiglitazone and glyburide

The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication.

The Role of Steroids in the Management of Uveitic Macular Edema

To review the role of steroids in the management of uveitic macular edema. Review of recent literature on the physiopathology of macular edema and clinical trials involving steroids as main treatment of uveitic macular edema. The steroid-glucocorticoid receptor complex regulates the action of specific steroids allowing transactivation or repression of a common as well as a unique set of genes. This specificity may help explain differences observed in the side effect profile of commonly used intraocular steroids (dexamethasone, fluocinolone, triamcinolone) whose ability to activate glucocorticoid receptors in model systems is very similar. Sustained delivery devices provide long-term remission of macular edema but with an increased incidence of cataract and glaucoma procedures. The exact incidence is dependent on the specific steroid, the mode of delivery, and the time since injection/placement.Steroid therapy is able to target many important pathways in uveitic macular edema, achieving good clinical results. Secondary adverse effects are still a matter of concern limiting their use. Steroid therapy remains a mainstay in the management of uveitic macular edema. Local administration precludes systemic adverse effects even though the risk of developing cataract or glaucoma remains an important issue. New slow release devices are thought to improve safety profile while keeping therapeutic advantages.