The imbalance between Treg and Th17 cells caused by FTY720 treatment in skin allograft rejection

OBJECTIVES: FTY720 modulates CD4(+)T cells by the augmentation of regulatory T cell activity, secretion of suppressive cytokines and suppression of IL-17 secretion by Th17 cells. To further understand the process of graft rejection/acceptance, we evaluated skin allograft survival and associated events after FTY720 treatment. METHODS: F1 mice (C57BL/6xBALB/c) and C57BL/6 mice were used as donors for and recipients of skin transplantation, respectively. The recipients were transplanted and either not treated or treated with FTY720 by gavage for 21 days to evaluate the allograft survival. In another set of experiments, the immunological evaluation was performed five days post-transplantation. The spleens, axillary lymph nodes and skin allografts of the recipient mice were harvested for phenotyping (flow cytometry), gene expression (real-time PCR) and cytokine (Bio-Plex) analysis. RESULTS: The FTY720 treatment significantly increased skin allograft survival, reduced the number of cells in the lymph nodes and decreased the percentage of Tregs at this site in the C57BL/6 recipients. Moreover, the treatment reduced the number of graft-infiltrating cells and the percentage of CD4(+) graft-infiltrating cells. The cytokine analysis (splenocytes) showed decreased levels of IL-10, IL-6 and IL-17 in the FTY720-treated mice. We also observed a decrease in the IL-10, IL-6 and IL-23 mRNA levels, as well as an increase in the IL-27 mRNA levels, in the splenocytes of the treated group. The FTY720-treated mice exhibited increased mRNA levels of IL-10, IL-27 and IL-23 in the skin graft. CONCLUSIONS: Our results demonstrated prolonged but not indefinite skin allograft survival by FTY720 treatment. This finding indicates that the drug did not prevent the imbalance between Tr1 and Th17 cells in the graft that led to rejection.

LIRAGLUTIDE: NEW RESULTS IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS

New drugs for type 2 diabetes that act on incretin metabolism have been shown to improve glycemic control, reduce body weight and have a low risk for hypoglycemia. Among these, liraglutide is the first glucagon-like peptide 1 (GLP-1) analogue approved for subcutaneous, once-daily administration. According to results from clinical trials, liraglutide is on attractive alternative for the early treatment of type 2 diabetes. The results of the LEAD (Liraglutide Effect and Action in Diabetes) study program demonstrated the efficacy and safety of liraglutide in terms of reduction of glycated hemoglobin (HbA(tc)) levels, significant loss of body weight that was maintained over the long term, better control of the lipid profile and systolic arterial pressure, reduction of the risk for hypoglycemia and reduction of cardiovascular risk. Moreover, the drug was demonstrated to be safe and can be co-administered with oral antidiabetic agents. The product's tolerability has been demonstrated, with nausea as the most common adverse event, which waned from the fourth week of treatment.

Relapse of Intravenous Drug Use Triggered by Enfuvirtide, a Parenteral Antiretroviral Medication

Fuzeon (R) (enfuvirtide; Hoffmann-LaRoche, Nutley, NJ) is a parenteral medication prescribed to antiretroviral-experienced HIV patients. Clinicians are frequently concerned when prescribing enfuvirtide to former drug addicts because of the risk of triggering relapse, however, no previous report has described this adverse event. We describe two HIV-infected patients, previously abstinent from injection drug use, who experienced relapse or near-relapse situations after starting treatment with enfuvirtide. Along with the concerns related to adherence and to injection site reactions, clinicians who prescribe enfuvirtide should consider and discuss the risk of triggering relapse among former or recovering drug addicts.

Monosodium glutamate neonatal treatment induces cardiovascular autonomic function changes in rodents

OBJECTIVES: The aim of this study was to evaluate cardiovascular autonomic function in a rodent obesity model induced by monosodium glutamate injections during the first seven days of life. METHOD: The animals were assigned to control (control, n = 10) and monosodium glutamate (monosodium glutamate, n = 13) groups. Thirty-three weeks after birth, arterial and venous catheters were implanted for arterial pressure measurements, drug administration, and blood sampling. Baroreflex sensitivity was evaluated according to the tachycardic and bradycardic responses induced by sodium nitroprusside and phenylephrine infusion, respectively. Sympathetic and vagal effects were determined by administering methylatropine and propranolol. RESULTS: Body weight, Lee index, and epididymal white adipose tissue values were higher in the monosodium glutamate group in comparison to the control group. The monosodium glutamate-treated rats displayed insulin resistance, as shown by a reduced glucose/insulin index (-62.5%), an increased area under the curve of total insulin secretion during glucose overload (39.3%), and basal hyperinsulinemia. The mean arterial pressure values were higher in the monosodium glutamate rats, whereas heart rate variability (>7 times), bradycardic responses (>4 times), and vagal (similar to 38%) and sympathetic effects (similar to 36%) were reduced as compared to the control group. CONCLUSION: Our results suggest that obesity induced by neonatal monosodium glutamate treatment impairs cardiac autonomic function and most likely contributes to increased arterial pressure and insulin resistance.

Use of Demonstrably Effective Therapies in the Treatment of Acute Coronary Syndromes: Comparison between Different Brazilian Regions. Analysis of the Brazilian Registry on Acute Coronary Syndromes (BRACE)

Background: Little is known in our country about regional differences in the treatment of acute coronary disease. Objective: To analyze the behavior regarding the use of demonstrably effective regional therapies in acute coronary disease. Methods: A total of 71 hospitals were randomly selected, respecting the proportionality of the country in relation to geographic location, among other criteria. In the overall population was regionally analyzed the use of aspirin, clopidogrel, ACE inhibitors / AT1 blocker, beta-blockers and statins, separately and grouped by individual score ranging from 0 (no drug used) to 100 (all drugs used). In myocardial infarction with ST elevation (STEMI) regional differences were analyzed regarding the use of therapeutic recanalization (fibrinolytics and primary angioplasty). Results: In the overall population, within the first 24 hours of hospitalization, the mean score in the North-Northeast (70.5 +/- 22.1) was lower (p < 0.05) than in the Southeast (77.7 +/- 29.5), Midwest (82 +/- 22.1) and South (82.4 +/- 21) regions. At hospital discharge, the score of the North-Northeast region (61.4 +/- 32.9) was lower (p < 0.05) than in the Southeast (69.2 +/- 31.6), Midwest (65.3 +/- 33.6) and South (73.7 +/- 28.1) regions; additionally, the score of the Midwest was lower (p < 0.05) than the South region. In STEMI, the use of recanalization therapies was highest in the Southeast (75.4%, p = 0.001 compared to the rest of the country), and lowest in the North-Northeast (52.5%, p < 0.001 compared to the rest of the country). Conclusion: The use of demonstrably effective therapies in the treatment of acute coronary disease is much to be desired in the country, with important regional differences.

Drug-targeting in combined cancer chemotherapy: tumor growth inhibition in mice by association of paclitaxel and etoposide with a cholesterol-rich nanoemulsion

Lipid nanoemulsions (LDE) may be used as carriers of paclitaxel (PTX) and etoposide (ETP) to decrease toxicity and increase the therapeutic action of those drugs. The current study investigates the combined chemotherapy with PTX and ETP associated with LDE. Four groups of 10-20 B16F10 melanoma-bearing mice were treated with LDE-PTX and LDE-ETP in combination (LDE-PTX + ETP), commercial PTX and ETP in combination (PTX + ETP), single LDE-PTX, and single LDE-ETP. PTX and ETX doses were 9 mu mol/kg administered in three intraperitoneal injections on three alternate days. In two control groups mice were treated with saline solution or LDE alone. Tumor growth, metastasis presence, cell-cycle distribution, blood cell counts and histological data were analyzed. Toxicity of all treatments was evaluated in mice without tumors. Tumor growth inhibition was similarly strong in all treatment groups. However, there was a greater reduction in the number of animals bearing metastases in the LDE-PTX + ETP group (30 %) in comparison to the PTX + ETP group (82 %, p < 0.05). Reduction of cellular density, blood vessels and increase of collagen fibers in tumor tissues were observed in the LDE-PTX + ETP group but not in the PTX + ETP group, and in both groups reduced melanoma-related anemia and thrombocytosis were observed. Flow cytometric analysis suggested that LDE-PTX + ETP exhibited greater selectivity to neoplastic cells than PTX-ETP, showing arrest (65 %) in the G(2)/M phase of the cell cycle (p < 0.001). Toxicity manifested by weight loss and myelosuppression was markedly milder in the LDE-PTX + ETP than in the PTX + ETP group. LDE-PTX + ETP combined drug-targeting therapy showed markedly superior anti-cancer properties and reduced toxicity compared to PTX + ETP.

Good clinical response to methotrexate treatment in a patient with fibroblastic rheumatism

Fibroblastic rheumatism (FR) is a rare disease first described by Chaouat (in Rev Rhum Mal Osteoartic 47: 345-351, 1980) and is characterized by a combination of rheumatologic and dermatological manifestations. Rheumatologic features are symmetrical polyarthralgias with joint stiffness, associated with cutaneous nodules and sclerodactyly. Histology shows an increased number of fibroblasts and a marked dermal fibrosis. A large number of treatments have been tried, but all of them have shown an unpredictable effect on FR. We report a Brazilian case of FR showing a good clinical response to methotrexate treatment. This drug may be considered an effective treatment in FR.

DM-1, sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate: a curcumin analog with a synergic effect in combination with paclitaxel in breast cancer treatment

This paper describes a new method for the preparation of sodium 4-[5-(4-hydroxy-3-methoxyphenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate, DM-1, and 3-oxo-penta-1,4-dienyl-bis (2-methoxy-phenolate), DM-2. The aim of this work was to evaluate the antitumor effects of DM-1 in adjuvant chemotherapy for breast cancer treatment. Mice bearing mammary adenocarcinomas (Ehrlich ascites tumors) were treated with paclitaxel alone, DM-1 alone, and paclitaxel + DM-1. Tumor samples were used to perform cytological analysis by the Papanicolaou method and apoptosis analysis by annexin V and phosphorylated caspase 3. The paclitaxel + DM-1 group had decreased tumor areas and tumor volumes, and the frequency of metastasis was significantly reduced. This caused a decrease in cachexia, which is usually caused by the tumor. Furthermore, treatment with paclitaxel + DM-1 and DM-1 alone increased the occurrence of apoptosis up to 40% in tumor cells, which is 35% more than in the group treated with paclitaxel alone. This cell death was mainly caused through phosphorylated caspase 3 (11% increase in paclitaxel + DM-1 compared to the paclitaxel group), as confirmed by reduced malignancy criteria in the ascitic fluid. DM-1 emerges as a potential treatment for breast cancer and may act as an adjuvant in chemotherapy, enhancing antitumor drug activity with reduced side effects.

Adverse Drug Events Leading Children to Hospital Emergency Care

To determine the incidence of adverse drug events (ADE) that resulted in the need for children's emergency care, a total of 23,286 pediatric emergency case notes were analyzed. They were selected on the basis of the ICD code indicating a possible ADE. ADEs were found in 13 case notes (0.06%), predominantly among girls and mainly in the 1 to 5 year age group. About half of the observed events occurred as a result of accidental ingestion, 27.3% were suicide attempts, and 27.3% arose due to the discontinuation of treatment. Antiepileptic drugs were those most often involved. Three (23%) were serious. The results suggest that children have easy access to medications and are involved in the majority of accidental occurrences. Using drugs involves risks, and drawing attention to such risks while prescribing and dispensing them fosters the sharing of responsibility and the empowerment of the users, measures necessary to health promotion.

Monitoring Drug Use Among HIV/AIDS Patients in Brazil: Should we Combine Self-Report and Urinalysis?

Illicit drug use in HIV-infected patients can be linked to impairment of physical and mental health, low health-related quality of life, and suboptimal adherence to HIV treatment. This study aimed to evaluate the correlation of self-report illicit drug use, urinalysis for cocaine and cannabis metabolites, and severity of dependence among HIV-infected patients on antiretroviral therapy (ART) in a treatment center in Brazil. Four hundred and thirty-eight outpatients of an HIV referral center were interviewed and assessed for drug use (lifetime, last year and last month). Urinalysis was performed to detect the presence of cocaine and cannabis metabolites in urine samples. Overall agreement between self-report and urinalysis was almost 68% for cannabis and higher than 85% for cocaine. Positive urinalysis was significantly associated with more than once a week cannabis (p < .0001) and cocaine (p <.0001) use during the last-month. Severity of Dependence Scale (SDS) properly predicted positive cocaine urinalysis results (area under the curve [AUC] = .81, p = .0001). Frequency of cannabis and cocaine use, SDS score degree and positive urinalysis for both drugs were correlated. Our findings suggest that positive self-report is a reliable predictor of positive urine sample both for cannabis and cocaine, but since the agreement was not perfect, there is a role for urine drug screening in the care of patients with HIV-related conditions.

Optimized Duration of Clopidogrel Therapy Following Treatment with the Endeavor Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) Trial: Rationale and design of a large-scale, randomized, multicenter study

Background Current recommendations for antithrombotic therapy after drug-eluting stent (DES) implantation include prolonged dual antiplatelet therapy (DAPT) with aspirin and clopidogrel >= 12 months. However, the impact of such a regimen for all patients receiving any DES system remains unclear based on scientific evidence available to date. Also, several other shortcomings have been identified with prolonged DAPT, including bleeding complications, compliance, and cost. The second-generation Endeavor zotarolimus-eluting stent (E-ZES) has demonstrated efficacy and safety, despite short duration DAPT (3 months) in the majority of studies. Still, the safety and clinical impact of short-term DAPT with E-ZES in the real world is yet to be determined. Methods The OPTIMIZE trial is a large, prospective, multicenter, randomized (1: 1) non-inferiority clinical evaluation of short-term (3 months) vs long-term (12-months) DAPT in patients undergoing E-ZES implantation in daily clinical practice. Overall, 3,120 patients were enrolled at 33 clinical sites in Brazil. The primary composite endpoint is death (any cause), myocardial infarction, cerebral vascular accident, and major bleeding at 12-month clinical follow-up post-index procedure. Conclusions The OPTIMIZE clinical trial will determine the clinical implications of DAPT duration with the second generation E-ZES in real-world patients undergoing percutaneous coronary intervention. (Am Heart J 2012;164:810-816.e3.)

Guanylate cyclase inhibition by methylene blue as an option in the treatment of vasoplegia after a severe burn. A medical hypothesis

Today it is known that severe burns can be accompanied by the phenomenon of vasoplegic syndrome (VS), which is manifested by persistent and diffuse vasodilation, hypotension and low vascular resistance, resulting in circulatory and respiratory failure. The decrease in systemic vascular resistance observed in VS is associated with excessive production of nitric oxide (NO). In the last 2 decades, studies have reported promising results from the administration of an NO competitor, methylene blue (MB), which is an inhibitor of the soluble guanylate cyclase (sGC), in the treatment of refractory cases of vasoplegia. This medical hypothesis rationale is focused on the tripod of burns/vasoplegia catecholamine resistant/methylene blue. This article has 3 main objectives: 1) to study the guanylate cyclase inhibition by MB in burns; 2) to suggest MB as a viable, safe and useful co-adjuvant therapeutic tool of fluid resuscitation, and; 3) to suggest MB as burns hypotensive vasoplegia amine-resistant treatment.

Celecoxib treatment does not alter recruitment and activation of osteoclasts in the initial phase of experimental tooth movement

In a previous study, we reported that the short-term treatment with celecoxib, a nonsteroidal anti-inflammatory drug (NSAID) attenuates the activation of brain structures related to nociception and does not interfere with orthodontic incisor separation in rats. The conclusion was that celecoxib could possibly be prescribed for pain in orthodontic patients. However, we did not analyze the effects of this drug in periodontium. The aim of this follow-up study was to analyze effects of celecoxib treatment on recruitment and activation of osteoclasts and alveolar bone resorption after inserting an activated orthodontic appliance between the incisors in our rat model. Twenty rats (400420 g) were pretreated through oral gavage with celecoxib (50 mg/kg) or vehicle (carboxymethylcellulose 0.4%). After 30 min, they received an activated (30 g) orthodontic appliance, set not to cause any palate disjunction. In sham animals, the appliance was immediately removed after introduction. All animals received ground food and, every 12 h, celecoxib or vehicle. After 48 h, they were anesthetized and transcardiacally perfused through the aorta with 4% formaldehyde. Subsequently, maxillae were removed, post-fixed and processed for histomorphometry or immunohistochemical analyses. As expected, incisor distalization induced an inflammatory response with certain histological changes, including an increase in the number of active osteoclasts at the compression side in group treated with vehicle (appliance: 32.2 +/- 2.49 vs sham: 4.8 +/- 1.79, P<0.05) and celecoxib (appliance: 31.0 +/- 1.45 vs sham: 4.6 +/- 1.82, P<0.05). The treatment with celecoxib did not modify substantially the histological alterations and the number of active osteoclasts after activation of orthodontic appliance. Moreover, we did not see any difference between the groups with respect to percentage of bone resorption area. Taken together with our previous results we conclude that short-term treatment with celecoxib can indeed be a therapeutic alternative for pain relieve during orthodontic procedures.

Muscle lesion treatment in Brazilian soccer players: theory vs. practice

Background: In this study we evaluated the rehabilitation profile of Brazilian soccer players which underwent lower limb muscle lesions. Methods: This is a descriptive investigation. We evaluated 139 professional soccer players (1724 years old). We evaluated the following variables: muscle lesion diagnosis, symptoms, non steroidal anti-inflammatory used, physiotherapy treatment, which physiotherapy recourses was used if treated and train adaptation. Results: In great part of the athletes muscle lesion remained between 2 weeks and 1 month. Around 54% were diagnosed by a physician; the other part was diagnosed by a physical therapist. Non steroidal anti-inflammatory were prescribed by physicians in 42% of the cases; in 7% the physical therapist prescribed the medication while in 49% of the cases the masseur prescribed the drug. More than 1/4 of the athletes received physiotherapy treatement between 48 hours and 5 days. Isometric exercise therapy was applied in 15% of the cases. 63% were not accompanied by the physiotherapist on their return to the field. 48% received massages immediately after injury. Conclusion: We presented discrepancy between the recommended theory described by several researches and the practice. We indicate the necessity of recycling in a general context the rehabilitation of muscle injuries.

In vivo evaluation of a metronidazole-containing gel for the adjuvant treatment of chronic periodontitis: preliminary results

The present study developed an experimental metronidazole-based gel and evaluated its efficacy for the adjuvant treatment of chronic periodontitis. Sixteen patients were randomly allocated into two groups of eight subjects according to the following proposed treatments: (1) scaling and root planing (active control) or (2) scaling and root planing and direct periodontal intrapocket application of 15% metronidazole-based gel in two sites (a parts per thousand yen5 mm in depth) (experimental group). Potential changes in the subgingival microbiota were assessed using a DNA Checkerboard method at three proposed times: baseline and following 7 or 30 days of drug administration. High-performance liquid chromatography (HPLC) monitored metronidazole concentrations in the crevicular fluid during treatment. The metronidazole experimental group presented lower bacterial counts than the control group at the three evaluated times (p < 0.01 for baseline, p < 0.001 for 7 or 30 days) when the target species were analyzed as a pool of bacteria. Samples revealed significantly lower counts 7 days after drug administration compared with baseline or after 30 days (p < 0.05). HPLC analysis detected gel 1 h after application. The metronidazole-based gel significantly decreased the total bacterial count at the three evaluated times. Periodontopathogenic species were not different after gel administration.