Therapeutic evaluation of free and liposome-loaded furazolidone in experimental visceral leishmaniasis

Drug delivery systems are promising pharmaceutical formulations used to improve the therapeutic index of drugs. In this study, we developed a liposomal formulation of furazolidone that targets Leishmania (Leishmania) chagasi amastigotes in a hamster model. Using laser scanning confocal microscopy, it was demonstrated that the liposomal drug co-localised with L. (L.) chagasi amastigotes within macrophages. Liposomal furazolidone administered intraperitoneally at 0.5 mg/kg for 12 consecutive days reduced spleen (74%) and liver (32%) parasite burden at a 100-fold lower dose than the free drug. Free furazolidone (50 mg/kg) also effectively reduced spleen (82.5%) and liver (85%) parasites; its in vitro activity against promastigotes and intracellular amastigotes demonstrated a high degree of parasite selectivity. Thus, furazolidone, both in the free and liposome-loaded formulation, is an effective inhibitor of L. (L.) chagasi, representing a possible cost-effective drug candidate for the treatment of visceral leishmaniasis. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Baroreflex deficit blunts exercise training-induced cardiovascular and autonomic adaptations in hypertensive rats

P>1. Baroreceptors regulate moment-to-moment blood pressure (BP) variations, but their long-term effect on the cardiovascular system remains unclear. Baroreceptor deficit accompanying hypertension contributes to increased BP variability (BPV) and sympathetic activity, whereas exercise training has been associated with an improvement in these baroreflex-mediated changes. The aim of the present study was to evaluate the autonomic, haemodynamic and cardiac morphofunctional effects of long-term sinoaortic baroreceptor denervation (SAD) in trained and sedentary spontaneously hypertensive rats (SHR). 2. Rats were subjected to SAD or sham surgery and were then further divided into sedentary and trained groups. Exercise training was performed on a treadmill (five times per week, 50-70% maximal running speed). All groups were studied after 10 weeks. 3. Sinoaortic baroreceptor denervation in SHR had no effect on basal heart rate (HR) or BP, but did augment BPV, impairing the cardiac function associated with increased cardiac hypertrophy and collagen deposition. Exercise training reduced BP and HR, re-established baroreflex sensitivity and improved both HR variability and BPV. However, SAD in trained SHR blunted all these improvements. Moreover, the systolic and diastolic hypertensive dysfunction, reduced left ventricular chamber diameter and increased cardiac collagen deposition seen in SHR were improved after the training protocol. These benefits were attenuated in trained SAD SHR. 4. In conclusion, the present study has demonstrated that the arterial baroreflex mediates cardiac disturbances associated with hypertension and is crucial for the beneficial cardiovascular morphofunctional and autonomic adaptations induced by chronic exercise in hypertension.

Fatal gemcitabine-induced pulmonary toxicity in metastatic gallbladder adenocarcinoma

Gemcitabine is a chemotherapy agent that may cause unpredictable side effects. In this report, we describe a fatal gemcitabine-induced pulmonary toxicity in a patient with gallbladder metastatic adenocarcinoma. A 72-year-old patient was submitted to an elective laparoscopic cholecystectomy, and a tubular adenocarcinoma in the gallbladder was incidentally diagnosed. CT scan and ultrasound before the surgery did not show any tumor. After the surgery a Pet scan was positive for a hot-spot in the left colon. The colonic lesion was conveniently removed and the histology evaluation confirmed the diagnosis of adenocarcinoma tubular. The patient was then submitted to three sections of 1,600 mg/m(2) of gemcitabine with intervals of 1 week. Three weeks later he developed severe respiratory distress. A helicoidal CT scan showed diffuse and severe interstitial pneumonitis, and lung biopsy confirmed accelerated usual interstitial pneumonia consistent with drug-induced toxicity. The patient presented unfavorable evolution with progressive worsening of respiratory function, hypotension, and renal failure. He died 1 month later in spite of methylprednisolone pulse therapy, large spectrum antimicrobial therapy, and full support of respiratory, hemodynamic and renal systems. Gemcitabine-induced pulmonary toxicity is usually a dramatic condition. Physicians should suspect pulmonary toxicity in patients with respiratory distress after gemcitabine chemotherapy, mainly in elderly patients.

The need for effective radiosentitizing agents: experience in patients with complete pathological response

Chemoradiation therapy is now considered the preferred initial treatment strategy for distal rectal cancer because of the observation of better local disease control and significant tumor downstaging. Downstaging has become an important clinical outcome as patients with complete pathological response are associated with improved survival. Even though radiation alone may result in low local recurrence rates, the use of additional radiosensitizing agents may provide an increase in local disease control in addition to improved tumor regression rates. Several compounds have been investigated in the setting of neoadjuvant multimodality treatment of rectal cancer with variable rates of treatment-related toxicity and complete pathological response. The balance between complete pathological response and toxicity should aid in the management decision for the use of radiosensitizing agents in the neoadjuvant setting for the treatment of rectal cancer. Anti-Cancer Drugs 22: 308-310 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Association Between Polymorphisms in GRIK2 Gene and Obsessive-Compulsive Disorder: A Family-Based Study

Several studies support a genetic influence on obsessive-compulsive disorder (OCD) etiology. The role of glutamate as an important neurotransmitter affecting OCD pathophysiology has been supported by neuroimaging, animal model, medication, and initial candidate gene studies. Genes involved in glutamatergic pathways, such as the glutamate receptor, ionotropic, kainate 2 (GRIK2), have been associated with OCD in previous studies. This study examines GRIK2 as a candidate gene for OCD susceptibility in a family-based approach. Probands had full DSM-IV diagnostic criteria for OCD. Forty-seven OCD probands and their parents were recruited from tertiary care OCD specialty clinics from France and USA. Genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes were analyzed using Haploview and FBAT software. The polymorphism at rs1556995 (P = 0.0027; permuted P-value = 0.03) was significantly associated with the presence of OCD. Also, the two marker haplotype rs1556995/rs1417182, was significantly associated with OCD (P = 0.0019, permuted P-value = 0.01). This study supports previously reported findings of association between proximal GRIK2 SNPs and OCD in a comprehensive evaluation of the gene. Further study with independent samples and larger sample sizes is required.

Similar Intracellular Peptide Profile of TAP1/beta 2 Microglobulin Double-Knockout Mice and C57BL/6 Wild-Type Mice as Revealed by Peptidomic Analysis

Cells produce and use peptides in distinctive ways. In the present report, using isotope labeling plus semi-quantitative mass spectrometry, we evaluated the intracellular peptide profile of TAP1/beta 2m(-/-) (transporter associated with antigen-processing 1/beta 2 microglobulin) double-knockout mice and compared it with that of C57BL/6 wild-type animals. Overall, 92 distinctive peptides were identified, and most were shown to have a similar concentration in both mouse strains. However, some peptides showed a modest increase or decrease (similar to 2-fold), whereas a glycine-rich peptide derived from the C-terminal of neurogranin (KGPGPGGPGGAGGARGGAGGGPSGD) showed a substantial increase (6-fold) in TAP1/beta 2m(-/-) mice. Thus, TAP1 and beta 2microglobulin have a small influence on the peptide profile of neuronal tissue, suggesting that the presence of peptides derived from intracellular proteins in neuronal tissue is not associated with antigens of the class I major histocompatibility complex. Therefore, it is possible that these intracellular peptides play a physiological role.

Bites by the colubrid snake Philodryas patagoniensis: A clinical and epidemiological study of 297 cases

We retrospectively analyzed 297 proven cases of Philodryas patagoniensis bites admitted to Hospital Vital Brazil (HVB), Butantan Institute, Sao Paulo, Brazil, between 1959 and 2008. Only cases in which the causative animal was brought and identified were included. Part of the snakes brought by the patients was still preserved in the collection maintained by the Laboratory of Herpetology. Of the 297 cases, in 199 it was possible to describe the gender of the snake, and seventy three (61.3%) of them were female. The length of snakes (snout-vent length) ranged from 160 to 1080 mm. In 117 snakes their state of preservation enabled the dissection and examination of their stomach contents. The stomach was empty in 106 snakes (89.1%). Most bites occurred in the seasons of spring and summer (n = 196, 66.0%) and during warmer periods of the day. The mean age of the victims was 24.1 +/- 15.1 years old and 206 (69.4%) patients were men. Around 92% of the patients sought medical care within 6 h after the bite. Both lower (n = 188, 63.3%) and upper limbs (n = 102, 34.3%) were most frequently bitten, especially the feet and hands (n = 205, 69.0%). The local clinical manifestations were pain (n = 151, 50.8%), transitory bleeding (n = 106, 35.7%), erythema (n = 47, 15.8%) and edema (n = 39, 13.1%). Ecchymosis was not observed. Only 7 (2.4%) patients reported systemic symptoms characterized by mild dizziness and 88 patients (29.6%) showed no evidence of envenoming. The whole blood clotting time was performed in 76 (25.6%) patients on admission and all of them had coagulable blood. Supportive treatment was offered to only 13.4% of patients, namely administration of antihistamines (n = 19, 6.4%) and analgesics (n = 12, 4.1%). Eight patients (2.7%) were mistreated with Bothrops antivenom before their admission to HVB. No sequels or relevant complications were observed in patients, and the prognostic was benign. Therefore, although P. patagoniensis accidents can cause mild local symptomatology, it is very important that health professionals know how to make the correct diagnosis to avoid unnecessary use of antivenom. (C) 2010 Elsevier Ltd. All rights reserved.

Protonectin (1-6): A novel chemotactic peptide from the venom of the social wasp Agelaia pallipes pallipes

Peptides constitute the largest group of Hymenoptera venom toxins; some of them interact with GPCR, being involved with the activation of different types of leukocytes, smooth muscle contraction and neurotoxicity. Most of these toxins vary from dodecapeptides to tetradecapeptides, amidated at their C-teminal amino acid residue. The venoms of social wasps can also contains some tetra-, penta-, hexa- and hepta-peptides, but just a few of them have been structurally and functionally characterized up to now. Protonectin (ILG-TILGLLKGL-NH(2)) is a polyfunctional peptide, presenting mast cell degranulation, release of lactate dehydrogenase (LDH) from mast cells, antibiosis against Gram-positive and Gram-negative bacteria and chemotaxis for polymorphonucleated leukocytes (PMNL), while Protonectin (1-6) (ILGTIL-NH(2)) only presents chemotaxis for PMNL However, the mixture of Protonectin (1-6) with Protonectin in the molar ratio of 1:1 seems to potentiate the biological activities dependent of the membrane perturbation caused by Protonectin, as observed in the increasing of the activities of mast cell degranulation, LDH releasing from mast cells, and antibiosis. Despite both peptides are able to induce PMNL chemotaxis, the mixture of them presents a reduced activity in comparison to the individual peptides. Apparently, when mixed both peptides seems to form a supra-molecular structure, which interact with the receptors responsible for PMNL chemotaxis, disturbing their individual docking with these receptors. In addition to this, a comparison of the sequences of both peptides suggests that the sequence ILGTIL is conserved, suggesting that it must constitute a linear motif for the structural recognition by the specific receptor which induces leukocytes migration. (C) 2010 Elsevier Ltd. All rights reserved.

Effects of anti-TNF therapy on glucose metabolism in patients with ankylosing spondylitis, psoriatic arthritis or juvenile idiopathic arthritis

The objective of this study was to evaluate the influence of anti-tumor necrosis factor (anti-TNF) in juvenile idiopathic arthritis (DA), ankylosing spondylitis (AS) or psoriatic arthritis (PsA). Sixty-two patients were investigated: 7 DA; 37 AS; and 18 PsA. Caucasian race accounted for 79% and 29% were female. Mean age was 40.4 +/- 12.6years. None of the patients had a history of diabetes, and none had used oral hypoglycemic agents or insulin. Treatment was with adalimumab, infliximab and etanercept. Glucose, inflammatory markers and prednisone dose were assessed at baseline, as well as after three and six months of treatment. The mean erythrocyte sedimentation rate was significantly lower at three months and six months than at baseline (13.7 +/- 18.0 and 18 +/- 22.5 vs. 27.9 +/- 23.4 mm; p = 0.001). At baseline, three months and six months, we found the following: mean C-reactive protein levels were comparable (22.1 +/- 22.7, 14.5 +/- 30.7 and 16.0 +/- 23.8 mg/L, respectively; p = 0.26); mean glucose levels remained unchanged (90.8 +/- 22.2 mg/dl, 89.5 +/- 14.6 mg/dl and 89.8 +/- 13.6 mg/dl, respectively; p = 0.91); and mean prednisone doses were low and stable (3.9 +/- 4.9 mg/day, 3.7 +/- 4.8 mg/day and 2.6 +/- 4.0 mg/day, respectively; p = 0.23). During the first six months of treatment, anti-TNF therapy does not seem to influence glucose metabolism in JIA, AS or PsA. (C) 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.

Systemic chemotherapy-induced microsatellite instability in the mononuclear cell fraction of women with breast cancer can be reproduced in vitro and abrogated by amifostine

Objectives Microsatellite instability (MSI) induction by alkylating agent-based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor-derived plasma-circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in-vitro model. Methods MSI was determined in pfDNA, PBMN cells and urine cell-free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF-7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine. Results We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF-7 and normal PBMN cells. In PBMN cells, ACHT-induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells. Conclusions ACHT induced MSI in PBMN cells and in tumour-derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.

Intrapericardial Ranolazine Prolongs Atrial Refractory Period and Markedly Reduces Atrial Fibrillation Inducibility in the Intact Porcine Heart

Introduction: Extensive experimental studies and clinical evidence (Metabolic Efficiency with Ranzolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction-36 [MERLIN TIMI-36] trial) indicate potential antiarrhythmic efficacy of the antianginal agent ranolazine. Delivery of agents into the pericardial space allows high local concentrations to be maintained in close proximity to myocardial tissue while systemic effects are minimized. Methods and Results: The effects of intrapericardial (IPC) administration of ranolazine (50-mg bolus) on right atrial and right ventricular effective refractory periods (ERP), atrial fibrillation threshold, and ventricular fibrillation threshold were determined in 17 closed-chest anesthetized pigs. IPC ranolazine increased atrial ERP in a time-dependent manner from 129 +/- 5.14 to 186 +/- 9.78 ms (P < 0.01, N = 7) but did not significantly affect ventricular ERP (from 188.3 +/- 4.6 to 201 +/- 4.3 ms (NS, N = 6). IPC ranolazine increased atrial fibrillation threshold from 4.8 +/- 0.8 to 28 +/- 2.3 mA (P < 0.03, N = 6) and ventricular fibrillation threshold (from 24 +/- 3.56 baseline to 29.33 +/- 2.04 mA at 10-20 minutes, P < 0.03, N = 6). No significant change in mean arterial pressure was observed (from 92.8 +/- 7.1 to 74.8 +/- 7.5 mm Hg, P < 0.125, N = 5, at 7 minutes). Conclusions: IPC ranolazine exhibits striking atrial antiarrhythmic actions as evidenced by increases in refractoriness and in fibrillation inducibility without significantly altering mean arterial blood pressure. Ranolazine`s effects on the atria appear to be more potent than those on the ventricles.

Quetiapine versus clomipramine in the augmentation of selective serotonin reuptake inhibitors for the treatment of obsessive-compulsive disorder: a randomized, open-label trial

After 12 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy with inadequate response, 10 patients received clomipramine and 11 received quetiapine as augmentation agents of the SSRI. The primary outcome measure was the difference between initial and final scores of the YaleBrown Obsessive-Compulsive Scale (Y-BOCS), rated in a blinded fashion, and the score of clinical global improvement (CGI-I). Statistical analyses were performed using nonparametric tests to evaluate treatment efficacy and the difference between treatment groups. Percentile plots were constructed with YBOCS scores from the clomipramine and quetiapine groups. Considering response a >= 35% reduction in the initial Y-BOCS score plus a rating of `much improved` or `very much improved` on CGI-I, four of eleven quetiapine patients and one out of ten clomipramine patients were classified as responders. The mean final Y-BOCS score was significantly lower than baseline in the quetiapine augmentation group (P = 0.023), but not in the clomipramine augmentation group (P = 0.503). The difference between groups showed a trend towards significance only at week 4, the mean Y-BOCS score being lower for those receiving quetiapine (P = 0.052). A difference between groups was also observed at week 4 according to percentile plots. These results corroborate previous findings of quetiapine augmentation efficacy in obsessive-compulsive disorder (OCD). Clomipramine augmentation did not produce a significant reduction in Y-BOCS scores. Higher target maximum dosages might have yielded different results.

Apolipoprotein E genotype and Cognition in Bipolar Disorder

Apolipoprotein E (APOE) has been extensively studied as a risk factor for sporadic and late onset Alzheimer`s Disease (AD). APOE allele *3, the most frequent variant, is not associated to cognitive dysfunction (CD) or to increased AD risk. Differently, the *4 allele is a well-established risk factor for CD, while the *2 allele is associated with survival and longevity. CD is an important feature of Bipolar Disorder (BD) and recent data suggest that CD may be one of its endophenotypes, although controversial results exist. The aim of this research is to study the association of APOE genotype (APOE) and neurocognitive function in a sample of drug free young BD-type I patients. Sample consisted of 25 symptomatic BD (type I) patients (age 18-35 years old). They were submitted to an extensive neuropsychological evaluation and genotyped for APOE. Subjects with allele *2 presented better cognitive performance. The presence of allele *4 was associated with worse performance in a few executive tasks. APOE *3*3 was associated with overall severe dysfunction on cognitive performance. In young individuals with nontreated BD-type I, APOE may predict cognitive performance. Further and larger studies on APOE and cognition in BD are required to clarify whether APOE is a BD cognitive endophenotype.

Erection induced by Tx2-6 toxin of Phoneutria nigriventer spider: Expression profile of genes in the nitric oxide pathway of penile tissue of mice

The peptides Tx2-5 and Tx2-6, isolated from the whole venom of ""armed-spider"" Phoneutria nigniventer venom, are directly linked with the induction of persistent and painful erection in the penis of mammals. The erection induced by Tx2-6 has been associated with the activation of nitric oxide synthases. There is a scarcity of studies focusing on the outcome of Tx2-6 at the molecular level, by this reason we evaluated the gene profile activity of this toxin at the nitric oxide (NO) pathway. After microarray analyses on cavernous tissue of mice inoculated with Tx2-6 we found that only 10.4% (10/96) of these genes were differentially expressed, showing a limited effect of the toxin on the NO pathway. We found the genes sparc, ednrb, junb, cdkn1a, bcl2, ccl5, abcc1 over-expressed and the genes sod1, s100a10 and fth1 under-expressed after inoculation of Tx2-6. The differential expressions of sparc and ednrb genes were further confirmed using real-time PCR. Interestingly, ednrb activates the L-arginine/NO/cGMP pathway that is involved in the relaxation of the cavernous body. Therefore the priapism induced by Tx2-6 is a consequence of a highly specific interference of this neurotoxin with the NO pathway. (C) 2009 Elsevier Ltd. All rights reserved.

Neuronal Correlates of Brain-derived Neurotrophic Factor Val66Met Polymorphism and Morphometric Abnormalities in Bipolar Disorder

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been proposed as a possible candidate for involvement in the pathophysiology of bipolar disorder ( BD). To determine whether an association exists between the BDNF Val66Met genotype and morphometric abnormalities of the brain regions involved in memory and learning in BD and healthy subjects. Forty-two BD patients and 42 healthy subjects were studied. Interactions between BDNF Val66Met genotype and diagnosis in gray ( GM) volumes were analyzed using an optimized voxel-based morphometry technique. Declarative memory function was assessed with the California Verbal Learning Test II. Left and right anterior cingulate GM volumes showed a significant interaction between genotype and diagnosis such that anterior cingulate GM volumes were significantly smaller in the Val/Met BD patients compared with the Val/Val BD patients (left P = 0.01, right P = 0.01). Within-group comparisons revealed that the Val/Met carriers showed smaller GM volumes of the dorsolateral prefrontal cortex compared with the Val/Val subjects within the BD patient (P = 0.01) and healthy groups (left P = 0.03, right P = 0.03). The Val/Met healthy subjects had smaller GM volumes of the left hippocampus compared with the Val/Val healthy subjects (P<0.01). There was a significant main effect of diagnosis on memory function (P = 0.04), but no interaction between diagnosis and genotype was found (P = 0.48). The findings support an association between the BDNF Val66Met genotype and differential gray matter content in brain structures, and suggest that the variation in this gene may play a more prominent role in brain structure differences in subjects affected with BD. Neuropsychopharmacology (2009) 34, 1904-1913; doi: 10.1038/npp.2009.23; published online 18 March 2009