Triazoles with inhibitory action on P2X7R impaired the acute inflammatory response in vivo and modulated the hemostatic balance in vitro and ex vivo.

OBJECTIVE: The present study aimed to investigate five triazole compounds as P2X7R inhibitors and evaluate their ability to reduce acute inflammation in vivo. MATERIAL: The synthetic compounds were labeled 5e, 8h, 9i, 11, and 12. TREATMENT: We administered 500 ng/kg triazole analogs in vivo, (1-10 µM) in vitro, and 1000 mg/kg for toxicological assays. METHODS: For this, we used in vitro experiments, such as platelet aggregation, in vivo experiments of paw edema and peritonitis in mice, and in silico experiments. RESULTS: The tested substances 5e, 8h, 9i, 11, and 12 produced a significant reduction in paw edema. Molecules 5e, 8h, 9i, 11, and 12 inhibited carrageenan-induced peritonitis. Substances 5e, 8h, 9i, 11, and 12 showed an anticoagulant effect, and 5e at a concentration of 10 µM acted as a procoagulant. All derivatives, except for 11, had pharmacokinetic, physicochemical, and toxicological properties suitable for substances that are candidates for new drugs. In addition, the ADMET risk assessment shows that derivatives 8h, 11, 5e, and 9i have high pharmacological potential. Finally, docking tests indicated that the derivatives have binding energies comparable to the reference antagonist with a competitive inhibition profile. CONCLUSIONS: Together, the results indicate that the molecules tested as antagonist drugs of P2X7R had anti-inflammatory action against the acute inflammatory response.

[Deferasirox and Complex Proximal Tubulopathy. Presentation of two clinical cases]. / Deferasirox y Tubulopatía Proximal Compleja. Presentación de dos casos clínicos.

INTRODUCTION: Treatment with iron chelators is essential for patients with iron overload secondary to repeated trans fusions. Deferasirox is the first once-daily oral active iron chelator. As a result, therapeutic adherence has improved, reducing the complications of iron overload, especially heart failure. However, it is not exempt from possible side effects, such as kidney involvement, which is more frequent in children. OBJECTIVE: To report 2 patients with Diamond-Blackfan anemia (DBA) who developed impaired renal function secondary to the administration of Deferasirox. CLINICAL CASES: Case 1. A 15-year-old adolescent diagnosed with DBA undergoing treatment with periodic transfusions and Deferasirox. During an acute gastroenteritis, she developed acute renal failure along with complex proximal tubu- lopathy. Case 2. A 5-year-old boy diagnosed with DBA receiving periodic transfusions and treatment with Deferasirox. He presented polyuria with laboratory abnormalities compatible with acute renal failure and proximal tubular dysfunction. In both cases, they were adequately hydrated and Deferasi rox was temporarily suspended, improving renal function. CONCLUSION: Based on these cases, close monitoring of renal and tubular function, as well as ferritin levels, is recommended in patients recei ving Deferasirox. In the presence of intercurrent processes, adequate hydration should be performed, and an early dose reduction or drug administration interruption should be considered in cases of kidney involvement.

New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial.

BACKGROUND: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. METHODS: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18-50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. FINDINGS: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73-99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73-99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64-95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65-95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67-97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64-95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. INTERPRETATION: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. FUNDING: Drugs for Neglected Diseases initiative (DNDi). TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Safety of Janus Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-mediated Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Uso de posaconazol en niños: experiencia en un hospital pediátrico de alta complejidad / Use of posaconazole in children: Experience in a tertiary pediatric hospital

La información sobre el uso de posaconazol en niños es escasa. Se realizó este estudio descriptivo retrospectivo entre agosto de 2010 y marzo de 2017 para evaluar las características clínicas, microbiológicas y la evolución de los pacientes tratados con posaconazol. Se incluyeron 16 niños. Mediana de edad: 161 meses (rango intercuartílico -RIC- 69-173 m). Todos tenían enfermedad subyacente y presentaban infección fúngica invasiva probada. Los aislamientos más frecuentes fueron Mucor spp. y Aspergillus spp. La dosis media de posaconazol fue 600 mg/día (400-800 mg/día) y la mediana de duración del tratamiento, 223 días (RIC 48-632). Diez pacientes presentaron efectos adversos, pero solo uno requirió suspensión del antifúngico debido a alteraciones hidroelectrolíticas.

There is limited information on the use of posaconazole in children. This retrospective and descriptive study was conducted to evaluate the clinical, microbiological characteristics and evolution of patients treated with posaconazole between August 2010 and March 2017. We included 16 children. Median age: 161 months (interquartile range -IQR-69-173m). All had underlying disease and a proven invasive fungal infection. The most frequent isolated were Mucor spp. and Aspergillus spp. The mean posaconazole dose was 600 mg /day (400-800 mg/day) and the median duration of treatment was 223 days (IQR 48-632). Ten patients had adverse effects, but only one required suspension of the antifungal treatment due to hydroelectrolytic disorders.

[Use of posaconazole in children: Experience in a tertiary pediatric hospital]. / Uso de posaconazol en niños: experiencia en un hospital pediátrico de alta complejidad.

There is limited information on the use of posaconazole in children. This retrospective and descriptive study was conducted to evaluate the clinical, microbiological characteristics and evolution of patients treated with posaconazole between August 2010 and March 2017. We included 16 children. Median age: 161 months (interquartile range -IQR- 69-173 m). All had underlying disease and a proven invasive fungal infection. The most frequent isolated were Mucor spp. and Aspergillus spp. The mean posaconazole dose was 600 mg/day (400-800 mg/day) and the median duration of treatment was 223 days (IQR 48-632). Ten patients had adverse effects, but only one required suspension of the antifungal treatment due to hydroelectrolytic disorders.

La información sobre el uso de posaconazol en niños es escasa. Se realizó este estudio descriptivo retrospectivo entre agosto de 2010 y marzo de 2017 para evaluar las características clínicas, microbiológicas y la evolución de los pacientes tratados con posaconazol. Se incluyeron 16 niños. Mediana de edad: 161 meses (rango intercuartílico ­RIC­ 69-173 m). Todos tenían enfermedad subyacente y presentaban infección fúngica invasiva probada. Los aislamientos más frecuentes fueron Mucor spp. y Aspergillus spp. La dosis media de posaconazol fue 600 mg/ día (400-800 mg/día) y la mediana de duración del tratamiento, 223 días (RIC 48-632). Diez pacientes presentaron efectos adversos, pero solo uno requirió suspensión del antifúngico debido a alteraciones hidroelectrolíticas.

Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial.

BACKGROUND: Chagas disease is a major neglected vector-borne disease. In this study, we investigated the safety and efficacy of three oral E1224 (a water-soluble ravuconazole prodrug) regimens and benznidazole versus placebo in adult chronic indeterminate Chagas disease. METHOD: In this proof-of-concept, double-blind, randomised phase 2 clinical trial, we recruited adults (18-50 years) with confirmed diagnosis of Trypanosoma cruzi infection from two outpatient units in Bolivia. Patients were randomised with a computer-generated randomisation list, which was stratified by centre and used a block size of ten. Patients were randomly assigned (1:1:1:1:1) to five oral treatment groups: high-dose E1224 (duration 8 weeks, total dose 4000 mg), low-dose E1224 (8 weeks, 2000 mg), short-dose E1224 (4 weeks + 4 weeks placebo, 2400 mg), benznidazole (60 days, 5 mg/kg per day), or placebo (8 weeks, E1224-matched tablets). Double-blinding was limited to the E1224 and placebo arms, and assessors were masked to all treatment allocations. The primary efficacy endpoint was parasitological response to E1224 at the end of treatment, assessed by PCR. The secondary efficacy endpoints were parasitological response to benznidazole at end of treatment, assessed by PCR; sustainability of parasitological response until 12 months; parasite clearance and changes in parasite load; incidence of conversion to negative response in conventional and non-conventional (antigen trypomastigote chemiluminescent ELISA [AT CL-ELISA]) serological response; changes in levels of biomarkers; and complete response. The primary analysis population consisted of all randomised patients by their assigned treatment arms. This trial is registered with ClinicalTrials.gov, number NCT01489228. FINDINGS: Between July 19, 2011, and July 26, 2012, we screened 560 participants with confirmed Chagas disease, of whom 231 were enrolled and assigned to high-dose E1224 (n=45), low-dose E1224 (n=48), short-dose E1224 (n=46), benznidazole (n=45), or placebo (n=47). Parasite clearance was observed with E1224 during the treatment phase, but no sustained response was seen with low-dose and short-dose regimens, whereas 13 patients (29%, 95% CI 16·4-44·3) had sustained response with the high-dose regimen compared with four (9%, 2·4-20·4) in the placebo group (p<0·0001). Benznidazole had a rapid and sustained effect on parasite clearance, with 37 patients (82%, 67·9-92·0) with sustained response at 12-month follow-up. After 1 week of treatment, mean quantitative PCR repeated measurements showed a significant reduction in parasite load in all treatment arms versus placebo. Parasite levels in the low-dose and short-dose E1224 groups gradually returned to placebo levels. Both treatments were well tolerated. Reversible, dose-dependent liver enzyme increases were seen with E1224 and benznidazole. 187 (81%) participants developed treatment-emergent adverse events and six (3%) developed treatment-emergent serious adverse events. Treatment-emergent adverse events were headaches, nausea, pruritus, peripheral neuropathy, and hypersensitivity. INTERPRETATION: E1224 is the first new chemical entity developed for Chagas disease in decades. E1224 displayed a transient, suppressive effect on parasite clearance, whereas benznidazole showed early and sustained efficacy until 12 months of follow-up. Despite PCR limitations, our results support increased diagnosis and access to benznidazole standard regimen, and provide a development roadmap for novel benznidazole regimens in monotherapy and in combinations with E1224. FUNDING: Drugs for Neglected Diseases initiative.

Deferasirox-induced urticarial vasculitis in a patient with myelodysplastic syndrome.

Deferasirox is an iron chelator agent used in the treatment of diseases with iron overload, such as thalassemia and myelodysplastic syndrome. Although the majority of adverse reactions of deferasirox involve gastrointestinal symptoms and increase in serum creatinine and transaminases, skin rashes, such as maculopapular and urticarial eruptions, have also been reported. This study reports a case of myelodysplastic syndrome with urticarial vasculitis due to deferasirox therapy. Drug eruption was been confirmed by means of a challenge test, together with histopathological and clinical findings. To the best of our knowledge, we report the first case of deferasirox-induced urticarial vasculitis. Physicians should be aware of the possibility of urticarial vasculitis on deferasirox therapy and the fact that the discontinuation of the drug generally results in improvement.

Deferasirox-induced urticarial vasculitis in a patient with myelodysplastic syndrome

Abstract Deferasirox is an iron chelator agent used in the treatment of diseases with iron overload, such as thalassemia and myelodysplastic syndrome. Although the majority of adverse reactions of deferasirox involve gastrointestinal symptoms and increase in serum creatinine and transaminases, skin rashes, such as maculopapular and urticarial eruptions, have also been reported. This study reports a case of myelodysplastic syndrome with urticarial vasculitis due to deferasirox therapy. Drug eruption was been confirmed by means of a challenge test, together with histopathological and clinical findings. To the best of our knowledge, we report the first case of deferasirox-induced urticarial vasculitis. Physicians should be aware of the possibility of urticarial vasculitis on deferasirox therapy and the fact that the discontinuation of the drug generally results in improvement.

Posaconazol (Noxafil®) suspensión y comprimidos no deben utilizarse indistintamente sin realizar un ajuste de dosis / Posaconazole (Noxafil®) suspension and tablets should not be used interchangeably without making a dose adjustment

El posaconazol es un antifúngico de amplio espectro de la familia de los triazólicos que se utiliza en el tratamiento y profilaxis de infecciones micóticas invasivas en pacientes de 13 años de edad o mayores, en las cuales otros tratamientos no han sido eficaces o tolerados. En junio de 2016 la Agencia Europea de Medicamentos y la Agencia Española de Medicamentos y Productos Sanitarios emitieron un alerta donde advierten que debido a diferencias en la frecuencia de dosificación, interacción con los alimentos y en los niveles plasmáticos alcanzados por el medicamento, los comprimidos y la suspensión de posaconazol no son intercambiables. (AU)

Posaconazole is a broad-spectrum triazole family antifungal used in the treatment and prophylaxis of invasive fungal infections in patients 13 years of age or older, in which other treatments have not been effective or tolerated. In June 2016 the European Medicines Agency and the Spanish Agency for Medicines and Health Products issued a warning alerting that because of differences in the frequency of dosing, interactions with food and plasma levels achieved by the drug, tablets and posaconazole suspension are not interchangeable. (AU)

Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1-yr Phase 2 study.

This open-label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12-month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.

Toxicidade materna e fetotoxicidade de ratas Wistar tratadas com Tebuconazol, durante o período organogênico / Maternal toxicity and fetotoxicity of Wistar rats exposed to Tebuconazole during the organogenic period

Tebuconazole is a synthetic agrochemical action systemic antifungal triazole. The maternal exposure to triazoles, during pregnancy, can cause adverse effects on maternal-placental-fetal united, resulting in alterations in the development of the fetus, thus it becomes essential to characterize these effects. This study aimed to analyze behavioral aspects of rats and physical development, sensory and motor litter. We used pregnant wistar rats treated orally with Tebuconazole doses (20 and 50 mg / kg / day) and rats in the Control Group with distilled water during the organogenic period (6th to 15th). After birth, there was the maternal reproductive performance: time of pregnancy, number of live pups, stillbirths, congenital malformations and the weight of the litter. Observed maternal behavior and lactation. Litters were weighed, daily from the 2nd to the 9th day after birth and the 10th dpn to 2 th of lactation, the individual weight. Also pups evaluated in the physical, sensoral development and motor activity in the open field. The results showed signs of acute toxicity in pregnant rats treated with 50 mg / kg / day occurring decrease in body weight gain, reducing the number of corpora lutea and maternal deaths as compared to controls and to the group 20mg/kg / days. In litters of rats exposed to doses of 20 and 50mg/kg/day there was a delay in the development of sensory and motor activity. Treatment with Tebuconazole, in subtoxic doses caused maternal toxicity, adverse effects on reproductive performance and fetotoxic.

O Tebuconazol é um agroquímico sintético de ação sistêmica, antifúngico do grupo dos triazóis. A exposição aos triazóis, durante o período gestacional, pode causar efeitos adversos na unidade materno-placentária-fetal, resultando em alterações no desenvolvimento do concepto, dessa forma torna-se imprescindível a caracterização desses efeitos. Objetivou-se analisar aspectos comportamentais das ratas e o desenvolvimento físico, sensorial e motor das ninhadas. Utilizou-se ratas Wistar prenhes, tratadas por via oral com o Tebuconazol nas doses (20 e 50 mg/kg/dia) e as ratas do Grupo Controle com água destilada, durante o período organogênico (6º ao 15º dia). Após o nascimento, observou-se a performance reprodutiva materna: tempo de prenhez, número de filhotes vivos, natimortos, malformações e ou anomalias e o peso total da ninhada. Observou o comportamento materno e a lactação. Pesaram-se as ninhadas diariamente, do 2º até o 9º dia-pós-nascimento e a partir do 10º dpn ao 21º dia de lactação verificou-se o peso individual. Também avaliou-se nos filhotes o desenvolvimento físico, a análise sensorial e a atividade motora em campo aberto. Os resultados mostraram sinais de intoxicação aguda nas ratas prenhes tratadas com a dose de 50 mg/kg/dia ocorrendo diminuição do ganho de peso corporal, redução do número de corpos lúteos e mortes maternas, quando comparados aos controles e ao grupo...

Toxicidade materna e fetotoxicidade de ratas Wistar tratadas com Tebuconazol, durante o período organogênico / Maternal toxicity and fetotoxicity of Wistar rats exposed to Tebuconazole during the organogenic period

Tebuconazole is a synthetic agrochemical action systemic antifungal triazole. The maternal exposure to triazoles, during pregnancy, can cause adverse effects on maternal-placental-fetal united, resulting in alterations in the development of the fetus, thus it becomes essential to characterize these effects. This study aimed to analyze behavioral aspects of rats and physical development, sensory and motor litter. We used pregnant wistar rats treated orally with Tebuconazole doses (20 and 50 mg / kg / day) and rats in the Control Group with distilled water during the organogenic period (6th to 15th). After birth, there was the maternal reproductive performance: time of pregnancy, number of live pups, stillbirths, congenital malformations and the weight of the litter. Observed maternal behavior and lactation. Litters were weighed, daily from the 2nd to the 9th day after birth and the 10th dpn to 2 th of lactation, the individual weight. Also pups evaluated in the physical, sensoral development and motor activity in the open field. The results showed signs of acute toxicity in pregnant rats treated with 50 mg / kg / day occurring decrease in body weight gain, reducing the number of corpora lutea and maternal deaths as compared to controls and to the group 20mg/kg / days. In litters of rats exposed to doses of 20 and 50mg/kg/day there was a delay in the development of sensory and motor activity. Treatment with Tebuconazole, in subtoxic doses caused maternal toxicity, adverse effects on reproductive performance and fetotoxic.(AU)

O Tebuconazol é um agroquímico sintético de ação sistêmica, antifúngico do grupo dos triazóis. A exposição aos triazóis, durante o período gestacional, pode causar efeitos adversos na unidade materno-placentária-fetal, resultando em alterações no desenvolvimento do concepto, dessa forma torna-se imprescindível a caracterização desses efeitos. Objetivou-se analisar aspectos comportamentais das ratas e o desenvolvimento físico, sensorial e motor das ninhadas. Utilizou-se ratas Wistar prenhes, tratadas por via oral com o Tebuconazol nas doses (20 e 50 mg/kg/dia) e as ratas do Grupo Controle com água destilada, durante o período organogênico (6º ao 15º dia). Após o nascimento, observou-se a performance reprodutiva materna: tempo de prenhez, número de filhotes vivos, natimortos, malformações e ou anomalias e o peso total da ninhada. Observou o comportamento materno e a lactação. Pesaram-se as ninhadas diariamente, do 2º até o 9º dia-pós-nascimento e a partir do 10º dpn ao 21º dia de lactação verificou-se o peso individual. Também avaliou-se nos filhotes o desenvolvimento físico, a análise sensorial e a atividade motora em campo aberto. Os resultados mostraram sinais de intoxicação aguda nas ratas prenhes tratadas com a dose de 50 mg/kg/dia ocorrendo diminuição do ganho de peso corporal, redução do número de corpos lúteos e mortes maternas, quando comparados aos controles e ao grupo...(AU)

Effect of calcitonin on anastrozole-induced bone pain during aromatase inhibitor therapy for breast cancer.

This study aimed to investigate calcitonin as an effective therapy for osteoporosis in patients with bone pain during the anastrozole treatment of breast cancer. Ninety-one patients, who were on anastrozole treatment for breast cancer and also suffered anastrozole-induced bone pain, were randomly divided into two groups: the calcitonin group received salmon calcitonin and Caltrate D, and the control group received Caltrate D. All patients were evaluated by the visual analogue scale (VAS) and underwent the dual energy x-ray absorptiometry test for bone mineral density (BMD), and serum osteocalcin (BGP), alkaline phosphatase (ALP), calcium (Ca), and phosphorus (P) were measured at three months before and after the treatment. Significant differences in serum Ca, P, BGP, and ALP were found in each group between before and after treatment (P < 0.05), while no differences between the calcitonin and control groups were found. No difference was observed in femur BMD between the two groups, or between before and after treatment in each group. There was a significant difference in spine BMD between before and after treatment in the control group (P < 0.05) but not in the calcitonin group, while no difference was found between the calcitonin and control groups. Futhermore, VAS score significantly declined in each group after treatment (P < 0.05), but much more in the calcitonin group than the control group (P < 0.05). Our finding suggests that calcitonin may alleviate bone pain during the anastrozole treatment of breast cancer but has no effect on bone loss during cancer treatment.

Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience.

OBJECTIVE: Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. METHODS: We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. RESULTS: Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). SIGNIFICANCE: Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology.

Safety and immunovirologic outcomes with maraviroc combination regimens in patients with a history of past treatment failures and virologic resistance in Brazil: an open-label, multicenter phase 3b study.

Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open-label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment-related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/µl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population.

Anastrozole and celecoxib for endometriosis treatment, good to keep them apart?

Endometriosis is a benign gynecological disease. Cyclooxygenase-2 (COX-2) and aromatase proteins have been shown to be overexpressed in eutopic endometrium from women suffering from this disease compared to disease-free women. Furthermore, inhibition of these molecules individually was demonstrated to have antiproliferative and proapoptotic effects both in vitro and in vivo in several models. In this study, the effect of combining celecoxib, a selective COX-2 inhibitor, and anastrozole, an aromatase inhibitor, on the implantation and growth of endometriotic like lesions in a murine model of endometriosis was evaluated. Endometriosis was surgically induced in female BALB/c mice. After 28 days of treatment with celecoxib, anastrozole, or their combination, animals were killed and lesions were counted, measured, excised, and fixed. Immunohistochemistry for proliferating cell nuclear antigen and CD34 was performed for assessment of cell proliferation and vascularization. TUNEL technique was performed for apoptosis evaluation. Celecoxib was the only treatment to significantly reduce the number of lesions established per mouse, their size and vascularized area. In addition, cell proliferation was significantly diminished and apoptosis was significantly enhanced by both individual treatments. When the therapies were combined, they reversed their effects. These results confirm that celecoxib and anastrozole separately decrease endometriotic growth, but when combined they might have antagonizing effects.

A reduced grade of liver fibros-steatosis after raltegravir, maraviroc and fosamprenavir in an HIV/HCV co-infected patient with chronic hepatitis, cardiomyopathy, intolerance to nelfinavir and a marked increase of serum creatine phosphokinase levels probably related to integrase inhibitor use / Grado reducido de fibroesteatosis tras la administración de raltegravir, maraviroc y fosamprenavir en un paciente co-infectado de VIH/VHC con hepatitis crónica, cardiomiopatía, intolerancia al nelfinavir y un aumento pronunciado de los niveles de creatina fosfoquinasa sérica probablemente debido al uso del inhibidor de la integrasa

The use of new antiretroviral drugs in HIV infection is particularly important in patients with intolerance or resistance to other antiretroviral agents. Raltegravir and maraviroc represent new, important resources in salvage regimens. A reduced grade of liver fibro-steatosis after a combination of raltegravir and maraviroc (second-line) has not been studied and the mechanism by which these new drug classes induced a marked reduction of grade of liver diseases is currently unknown. In the present case report, nested in an ongoing multicentre observational study on the use of new antiretroviral inhibitors in heavy treatment-experienced HIV patients, we evaluated the correlation between a "short therapeutic regimen" raltegravir, maraviroc and fosamprenavir and liver diseases. The aim of this report is to describe the use of a three-drug regimen based on two novel-class antiretroviral agents (raltegravir and maraviroc) plus the protease inhibitor fosamprenavir, in an experienced HIV-infected patient with chronic progressive hepatitis C complicated by liver fibrosis; an overwhelming increased serum creatine kinase level occurred during treatment, and is probably related to integrase inhibitor administration. At present no information is available regarding this correlation.

El uso de nuevos medicamentos antiretrovirales para la infección por VIH es particularmente importante en los pacientes con intolerancia o resistencia a otros agentes antiretrovirales. Raltegravir (RTV) y maraviroc (MRV) representan nuevos e importantes recursos en las terapias de salvamento. Un grado reducido de fibroesteatosis hepática después de una combinación de raltegravir y maraviroc (terapia de segunda línea) no ha sido estudiado, y el mecanismo por el cual estas nuevas clases de droga indujeron una marcada reducción de grado de las enfermedades hepáticas se desconoce hasta el momento. Como parte de la realización en curso de un estudio observacional multicentro acerca del uso de nuevos inhibidores antiretrovirales en pacientes de VIH altamente experimentados en el tratamiento, en el presente reporte de caso se evalúa la correlación entre un "régimen terapéutico corto" (raltegravir, maraviroc y fosamprenavir) y las enfermedades del hígado. El objetivo de este reporte es describir el uso de un régimen de tres medicamentos - basado en dos agentes antiretrovirales de nuevo tipo (raltegravir y maraviroc) además del fosamprenavir inhibidor de la proteasa - en un paciente de VIH experimentado. El paciente también sufre de hepatitis C evolutiva, progresiva, crónica, complicada por fibrosis hepática. Durante el tratamiento, se produjo un aumento extraordinario del nivel de creatina quinasa sérica, el cual probablemente esta relacionado con la administración del inhibidor de la integrasa. Actualmente no hay información disponible con respecto a esta correlación.