Medical Grade Honey as a Promising Treatment to Improve Ovarian Tissue Transplantation.

Ovarian tissue cryopreservation is a female fertility preservation technique that presents major challenges for the maintenance of follicular viability after transplantation. The aim of this study was to evaluate and compare the application of L-Mesitran Soft®, a product containing 40% medical grade honey (MGH), with other strategies to improve ovarian grafts' viability. For this purpose, bovine ovarian tissue was vitrified, warmed and randomly assigned to culture groups: (1) control, (2) MGH 0.2% in vitro, (3) MGH in vivo (direct application in the xenotransplantation), (4) vascular endothelial growth factor (VEGF 50 ng/mL) and (5) vitamin D (100 Nm), during a 48 h period. A sixth group (6) of fragments was thawed on transplantation day and was not cultured. The tissue was xenotransplanted into immunodeficient (Rowett nude homozygous) ovariectomized rats. Grafts were analyzed 48 h after culture, and 7 and 28 days after transplantation. The tissue was subjected to histological and immunohistochemical analysis. Treatments using MGH showed the highest angiogenic and cell proliferation stimulation, with cellular apoptosis, within a healthy cellular turnover pathway. In conclusion, MGH should be considered as a potentially effective and less expensive strategy to improve ovarian tissue transplantation.

Effects of feeding rumen-protected linseed fat to postpartum dairy cows on plasma n-3 polyunsaturated fatty acid concentrations and metabolic and reproductive parameters.

High-yielding dairy cows experience a negative energy balance and inflammatory status during the transition period. Fat supplementation increases diet energy density, and plasma n-3 polyunsaturated fatty acids (PUFA) have been proposed to improve immune function. This study tested the hypothesis that dietary supplementation with a rumen-protected and n-3 PUFA-enriched fat could ameliorate both the energetic deficit and immune status of postpartum high-yielding dairy cows, improving overall health and reproductive efficiency. At 11 d in milk (DIM), cows were randomly allocated to groups (1) n-3 PUFA (n = 29), supplemented with encapsulated linseed oil supplying additional up to 64 g/d (mean 25 ± 4 g/d) of α-linolenic acid (ALA), or (2) control (n = 31), supplemented with hydrogenated palm oil without ALA content. Fat supplements of the n-3 PUFA and control groups were available through an automated, off-parlor feeding system, and intake depended on the cow's feeding behavior. Plasma ALA concentrations were higher in n-3 PUFA than control cows, following a linear relation with supplement ingestion, resulting in a lower n-6/n-3 ratio in plasma. Metabolic parameters (body condition score and glucose and ß-hydroxybutyric acid blood concentrations) were unaffected, but milk yield improved with increased intake of fat supplements. Plasma total adiponectin concentrations were negatively correlated with ingestion of n-3 PUFA-enriched fat supplement, following a linear relation with intake. Conception rate to first AI increased with higher intake of both fats, but a decrease of calving-to-conception interval occurred only in n-3 PUFA cows. Postpartum ovarian activity and endometrial inflammatory status at 45 DIM were unaffected. In conclusion, this study evinced a positive linear relation between rumen-protected linseed fat intake and plasma n-3 PUFA concentrations, which modulated adiponectin expression and improved reproductive parameters.

Bioactivity screening of pinhão (Araucaria Angustifolia (Bertol.) Kuntze) seed extracts: the inhibition of cholinesterases and α-amylases, and cytotoxic and anti-inflammatory activities.

The objective of this work was to determine the potential bioactive properties of extracts from bio-residues of pinhão (Araucaria angustifolia (Bertol.) Kuntze) seeds, namely the α-amylase and cholinesterase inhibition, cytotoxicity, and anti-inflammatory properties. The pinhão extracts evaluated were obtained from cooking water (CW) and as an ethanolic extract from residual pinhão seed shells (PS). Catechin was the major compound found in both extracts. The PS extract presented higher antioxidant levels and the better inhibition of human salivary and porcine pancreatic α-amylases when compared to the CW extract. Also, based on in vivo evaluations, the PS extract did not differ significantly from acarbose when compared to a control group. The most potent inhibitor of cholinesterases was the CW extract. No cytotoxicity toward normal cells was detected, and neither extract showed anti-inflammatory activity. The PS extract presented cytotoxic activity toward non-small-cell lung, cervical, hepatocellular and breast carcinoma cell lines. Overall, the results demonstrated the potential bioactivity of extracts obtained from pinhão bio-residues.

"Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study".

OBJECTIVE: The vitamin D endocrine system may have a variety of actions on cells and tissues involved in COVID-19 progression especially by decreasing the Acute Respiratory Distress Syndrome. Calcifediol can rapidly increase serum 25OHD concentration. We therefore evaluated the effect of calcifediol treatment, on Intensive Care Unit Admission and Mortality rate among Spanish patients hospitalized for COVID-19. DESIGN: Parallel pilot randomized open label, double-masked clinical trial. SETTING: University hospital setting (Reina Sofia University Hospital, Córdoba Spain.) PARTICIPANTS: 76 consecutive patients hospitalized with COVID-19 infection, clinical picture of acute respiratory infection, confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale (recommending hospital admission in case of total score > 1). PROCEDURES: All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 h on the first day, and 200 mg every 12 h for the following 5 days), azithromycin (500 mg orally for 5 days. Eligible patients were allocated at a 2 calcifediol:1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission. Outcomes of effectiveness included rate of ICU admission and deaths. RESULTS: Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50 %) p value X2 Fischer test p < 0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95 %CI 0.002-0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95 %CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged. CONCLUSION: Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer.

Notch signaling in mouse blastocyst development and hatching.

BACKGROUND: Mammalian early embryo development requires a well-orchestrated interplay of cell signaling pathways. Notch is a major regulatory pathway involved in cell-fate determination in embryonic and adult scenarios. However, the role of Notch in embryonic pre-implantation development is controversial. In particular, Notch role on blastocyst development and hatching remains elusive, and a complete picture of the transcription and expression patterns of Notch components during this time-period is not available. RESULTS: This study provided a comprehensive view on the dynamics of individual embryo gene transcription and protein expression patterns of Notch components (receptors Notch1-4; ligands Dll1 and Dll4, Jagged1-2; and effectors Hes1-2), and their relationship with transcription of gene markers of pluripotency and differentiation (Sox2, Oct4, Klf4, Cdx2) during mouse blastocyst development and hatching. Transcription of Notch1-2, Jagged1-2 and Hes1 was highly prevalent and dynamic along stages of development, whereas transcription of Notch3-4, Dll4 and Hes2 had a low prevalence among embryos. Transcription levels of Notch1, Notch2, Jagged2 and Hes1 correlated with each other and with those of pluripotency and differentiation genes. Gene transcription was associated to protein expression, except for Jagged2, where high transcription levels in all embryos were not translated into protein. Presence of Notch signaling activity was confirmed through nuclear NICD and Hes1 detection, and downregulation of Hes1 transcription following canonical signaling blockade with DAPT. In vitro embryo culture supplementation with Jagged1 had no effect on embryo developmental kinetics. In contrast, supplementation with Jagged2 abolished Jagged1 transcription, downregulated Cdx2 transcription and inhibited blastocyst hatching. Notch signaling blockade by DAPT downregulated transcription of Sox2, and retarded embryo hatching. CONCLUSION: Transcription of Notch genes showed a dynamic pattern along blastocyst development and hatching. Data confirmed Notch signaling activity, and lead to the suggestion that Notch canonical signaling may be operating through Notch1, Notch3, Jagged1 and Hes1. Embryo culture supplementation with Jagged1 and Jagged2 unveiled a possible regulatory effect between Jagged1, Cdx2 and blastocyst hatching. Overall, results indicate that a deregulation in Notch signaling, either by its over or under-activation, affects blastocyst development and hatching.

Kaolin-induced hydrocephalus causes acetylcholinesterase activity dysfunction following hypothalamic damage in infant rats.

In hydrocephalus, the progressive accumulation of cerebrospinal fluid (CSF) causes dilatation of the lateral ventricles affecting the third ventricle and diencephalic structures such as the hypothalamus. These structures play a key role in the regulation of several neurovegetative functions by the production of the hormones. Since endocrine disturbances are commonly observed in hydrocephalic children, we investigated the impact of progressive ventricular dilation on the hypothalamus of infant rats submitted to kaolin-induced hydrocephalus. Seven-day-old infant rats were submitted to hydrocephalus induction by kaolin 20% injection method. After 14 days, the animals were decapitated and brain was collected to analyze mitochondrial function, neuronal activity by acetylcholinesterase (AChE) enzyme, oxidative damage, glial activation, and, neurotransmission-related proteins and anti-apoptotic processes in the hypothalamus. The hydrocephalic animals showed reduction in respiratory rates in the States of phosphorylation (P < 0.01) and non-phosphorylation (P < 0.05); increase in AChE activity in both the cytosol (P < 0.05) and the membrane (P < 0.01); decrease in synaptophysin (P < 0.05) and Bcl-2 (P < 0.05) contents and; increase in protein carbonyl (P < 0.01), GFAP (P < 0.01) and Iba-1 (P < 0.05) levels. The results demonstrate that ventricular dilation causes hypothalamic damage characterized by cholinergic dysfunction and suggests further investigation of the synthesis and secretion of hormones to generate new approaches and to assist in the treatment of hydrocephalic patients with hormonal alterations.

Central leukotrienes modulate fever tolerance to LPS in rats.

Leukotrienes mediate several inflammatory events such as neutrophil chemoattraction, leukocyte adhesion, and central-release of cytokines and fever. However, there is no information available about their putative role in lipopolysaccharide (LPS) tolerance. The rational of the present study was to find out if central leukotrienes are involved in the development of LPS tolerance. Thus, we inhibited central leukotriene synthesis in tolerant rats using a pharmacological tool, i.e., a selective inhibitor of leukotriene synthesis MK-886 injected into the third ventricle (3V) of rats. Body core temperature (Tb) was measured using a datalogger placed inside the abdominal cavity. A low-dose of LPS (100 µg/kg ip) was given for 4 consecutive days to induce LPS tolerance. At day 4, rats received a microinjection of MK-886 into the 3V immediately before LPS, whereas control groups were treated with vehicle (saline). We observed that LPS failed to induce plasma cytokines surges, increased hypothalamic PGE2 levels and fever 3 days post LPS treatment, aptly characterizing the tolerance. When MK-886 was given to control rats treated with saline, no significant change in Tb was observed. However, a full LPS-induced fever was observed in tolerant rats pretreated with MK-886, which was associated with an enhancement in the hypothalamic PGE2 levels, that were not accompanied by plasma cytokines (IL-1ß, and IL-6) and PGE2 surges. These data are consistent with the notion that central leukotrienes play a role in fever tolerance to LPS.

Clinical and translational pharmacology of drugs for the prevention and treatment of bone metastases and cancer-induced bone loss.

Bone disease is a frequent event in cancer patients, both due to cancer spread to bone and to cancer therapies. Bone is the organ most frequently affected by metastatic disease when considering the two most frequent cancers in the Western world (breast and prostate cancers). Bone metastases can have a substantial detrimental effect on patients' quality of life, as well as significant morbidity due to complications collectively known as skeletal-related events (SREs), which include hypercalcaemia, pathological fractures, spinal cord compression, and need of radiotherapy or surgery to the bone. These have been successfully mitigated with the development of bone-targeted agents (BTAs; bisphosphonates and denosumab), focused on inhibiting osteoclast activity. The potential direct antitumour effect of bisphosphonates, as well as the impact of osteoclast inhibition with subsequent decrease in bone metabolism, have also propelled investigation on the role of BTAs in preventing cancer relapse in bone. In this review, the authors aimed to discuss the role of BTAs in the treatment and prevention of bone metastases, as well as their potential value in preventing cancer treatment-induced bone loss (CTIBL). The review will focus on breast and prostate cancers, with the aim of providing the most relevant clinical data emerging from bench to bedside translational research in the field of cancer-induced bone disease.

Antidiarrheal activity of a novel sulfated polysaccharide from the red seaweed Gracilaria cervicornis.

ETHNOPHARMACOLOGICAL RELEVANCE: The use of marine seaweeds as a source of natural compounds with medicinal purposes is increasing in Western countries in the last decades, becoming an important alternative in the traditional medicine of many developing countries, where diarrhea still remains a severe public health problem, with high rates of mortality and morbidity. Sulfated polysaccharides (PLS) extracted from red seaweeds can exhibit therapeutic effects for the treatment of gastrointestinal disorders. Thus, the pharmacological properties of the PLS from Gracilaria cervicornis, an endemic seaweed found in the Brazilian northeast coast, was evaluated as an alternative natural medication for diarrhea. AIM OF THE STUDY: This study aimed to evaluate the antidiarrheal activity of sulfated polysaccharides (PLS) extracted from the red seaweed G. cervicornis in Swiss mice pre-treated with castor oil or cholera toxin. MATERIALS AND METHODS: The seaweed Gracilaria cervicornis was collected at Flecheiras beach (city of Trairí, State of Ceará, Brazil) and the PLS was obtained through enzymatic extraction and administered in mice (25-30 g) before diarrhea induction with castor oil or cholera toxin. For the evaluation of the total number of fecal output and diarrheal feces, the animals were placed in cages lined with adsorbent material. The evaluation of intestinal fluid accumulation (enteropooling) on castor oil-induced diarrhea in mice occurred by dissecting the small intestine and measuring its volume. The determination of Na+/K+-ATPase activity was measured in the small intestine supernatants by colorimetry, using commercial biochemistry kits. The gastrointestinal motility was evaluated utilizing an activated charcoal as a food tracer. The intestinal fluid secretion and chloride ion concentration were evaluated in intestinal closed loops in mice with cholera toxin-induced secretory diarrhea. The binding ability of PLS with GM1 and/or cholera toxin was evaluated by an Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: The G. cervicornis PLS showed antidiarrheal effects in both acute and secretory diarrhea, reducing the total number of fecal output, diarrheic stools, intestinal fluid accumulation, and increasing small intestine Na+/K+-ATPase activity on castor oil-induced diarrhea. However, the PLS did not affect gastrointestinal motility, indicating that this compound has a different action mechanism than loperamide. In secretory diarrhea, the PLS decreased intestinal fluid secretion and small intestine chloride excretion, binding with GM1 and/or cholera toxin and blocking their attachment to the enterocyte cell surface. CONCLUSIONS: In conclusion, PLS has a significant antidiarrheal effect in acute and secretory diarrhea. Further investigation is needed towards its use as a natural medicine to treat diarrhea.

Impairment of osmotic challenge-induced neurohypophyseal hormones secretion in sepsis survivor rats.

BACKGROUND/PURPOSE: Recent studies have reported that sepsis survivors show impaired central nervous system functions. The osmoregulation in this post-sepsis condition has not been well investigated. In the present study, we evaluated the secretion of neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin (OT), and water intake induced by osmotic challenge in survivor rats. METHODS: Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP). Five days after CLP surgery, the survivor and naive animals were stimulated with an osmotic challenge consisting of hypertonic saline administration. Thirty minutes later, blood and brain were collected for determination of osmolality, nitrite, interleukin (IL)-1ß, IL-6, AVP and OT levels and c-fos expression analysis of hypothalamic supraoptic nuclei (SON), respectively. In another set of sepsis survivor animals, water intake was measured for 240 min after the osmotic stimulus. RESULTS: High levels of nitrite and IL-1ß, but not IL-6, were found in the plasma of sepsis survivors and this long-term systemic inflammation was not altered by the osmotic challenge. Moreover, the AVP and OT secretion (but not the osmolality) and c-fos expression in SON were significantly attenuated in CLP survivor animals. Additionally, there was no alteration in the water intake response induced by osmotic challenge in the sepsis survivor group. CONCLUSION: The results suggest that the inflammatory components mediated a persistent impairment in the component of the osmoregulatory reflex affecting the secretion of neurohypophyseal hormones in sepsis survivor animals.

Anti-diarrhoeal therapeutic potential and safety assessment of sulphated polysaccharide fraction from Gracilaria intermedia seaweed in mice.

Sulphated polysaccharides extracted from algae have been extensively studied for their diverse biological activities. Thus, the purpose of this study was to evaluate the chemical composition, the anti-diarrhoeal effect and acute toxicity of a sulphated polysaccharide fraction obtained from Gracilaria intermedia (SP-Gi). Initially, the FT-IR of SP-Gi revealed to be an agaran with sulphation at C-6 of the l-galactosyl residues. The anti-diarrhoeal activity of SP-Gi was evaluated in a castor oil-induced diarrhoea model. The effects of SP-Gi on enteropooling, Na +-K +-ATPase activity, gastrointestinal transit, and gastric emptying were then examined. Subsequently, the effect of SP-Gi on diarrhoea induced by cholera toxin (CT) and Escherichia coli was examined. In addition, an acute toxicity test was conducted in accordance with OECD guideline 423. Pre-treatment with SP-Gi reduces the total faeces, total diarrhoeal faeces, and enteropooling. SP-Gi (30mg/kg p.o.) increased Na+/K+-ATPase activity and reduced gastrointestinal transit through anticholinergic mechanisms. ELISA demonstrated that SP-Gi can interact with GM1 receptors and CT. SP-Gi reduced diarrhoea induced by E. coli and prevented weight loss in the animals. Moreover, SP-Gi did not induce any toxicity signs. These results suggest that SP-Gi is a possible candidate for the treatment of diarrhoeal illnesses.

Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial Activation.

Previous studies have shown that in the early phase of sepsis, the plasma concentration of arginine vasopressin (AVP) is increased, but in the late phase, its levels remain inadequately low, despite of persistent hypotension. One hypothesis suggested for this relative deficiency is apoptosis of vasopressinergic neurons. Here, we investigated apoptosis pathways in the hypothalamus during sepsis, as well as mechanisms underlying this process. Male Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. After 6 and 24 h, the animals were decapitated and brain and blood were collected to assess hypothalamic apoptotic markers, IFN-γ plasma levels, and evidence for breakdown of the blood-brain barrier (BBB). Sepsis caused a decrease in mitochondrial antiapoptotic proteins (Bcl-2, Bcl-xL) in the hypothalamus, but had no effect on markers of cell death mediated by death receptors or immune cells. In the supraoptic nuclei of these animals, microglia morphology was consistent with activation, associated with an increase in plasma IFN-γ. A transitory breakdown of BBB in the hypothalamus was seen at 6 h following CLP. The results indicate that the intrinsic but not extrinsic apoptosis pathway is involved in the cell death observed in vasopressinergic neurons, and that this condition is temporally associated with microglial activation and BBB leaking.

Improving quality of life in patients with advanced cancer: Targeting metastatic bone pain.

Metastatic bone disease in patients with advanced cancer is frequently associated with skeletal complications. These can be debilitating, causing pain, impaired functioning and decreased quality of life, as well as reduced survival. This review considers how the management of metastatic bone pain might be optimised, to limit the considerable burden it can impose on affected patients. Cancer-related pain is notoriously under-reported and under-treated, despite the availability of many therapeutic options. Non-opioid and opioid analgesics can be used; the latter are typically administered with radiotherapy, which forms the current standard of care for patients with metastatic bone pain. Surgery is appropriate for certain complicated cases of metastatic bone disease, and other options such as radiopharmaceuticals may provide additional relief. Treatments collectively referred to as bone-targeted agents (BTAs; bisphosphonates and denosumab) can offer further pain reduction. Initiation of therapy with BTAs is recommended for all patients with metastatic bone disease because these agents delay not only the onset of skeletal-related events but also the onset of bone pain. With evidence also emerging for pain control properties of new anticancer agents, the potential to individualise care for these patients is increased further. Optimisation of care depends on physicians' thorough appreciation of the complementary benefits that might be achieved with the various agents, as well as their limitations. Appropriate anti-tumour treatment combined with early initiation of BTAs and adequate analgesia plays a key role in the holistic approach to cancer pain management and may minimise the debilitating effects of metastatic bone pain.

Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis.

In our previous work, we demonstrated that the intracerebroventricular (i.c.v.) injection of an interleukin-1 receptor antagonist (IL-1ra) prevented the impairment in vasopressin secretion and increased survival rate in septic rats. Additionally, we saw a reduction in nitric oxide (NO) levels in cerebroventricular spinal fluid (CSF), suggesting that the IL-1ra prevents apoptosis that seems to occur in vasopressinergic neurons. Here, we investigated the effect of IL-1ra pre-treatment on the sepsis-induced increase in oxidative stress markers in the hypothalamus of rats. The animals were pre-treated by an i.c.v. injection of IL-1ra (9 nmol) or vehicle (0.01 M PBS) before being subjected to cecal ligation and puncture (CLP) or left as control (sham-operation or naive). After 4, 6, and 24 h, the animals were decapitated (n = 9/group) and the brain removed for hypothalamic tissue collection. Transcript and protein levels of IL-1, inducible nitric oxide synthase (iNOS), caspase-3, and hypoxia-inducible factor 1-alpha (HIF-1α) were measured by quantitative polymerase chain reaction (qPCR) and western blot, respectively. Hypothalamic mRNA levels of all these genes were significantly (P < 0.005) increased at 4, 6, and 24 h CLP, as compared to sham-operated animals. IL-1ra pre-treatment in these CLP animals significantly decreased IL-1 gene expression at all time points and also of iNOS, caspase-3, and HIF-1α at 24 h when compared to vehicle-treated CLP animals. The effect of the pre-treatment on protein expression was most clearly seen for IL-1ß and iNOS at 24 h. Our results showed that blocking the IL-1-IL-1r signaling pathway by central administration of an IL-1ra decreases hypothalamic oxidative stress markers during sepsis.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.

PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.

PURPOSE: This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. PATIENTS AND METHODS: Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS: Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading. CONCLUSION: Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

Toxicidad aguda de un extracto acuoso de Boldoa purpurascens Cav en el modelo de sube y baja en ratas / Acute toxicity of an aqueous extract of Boldoa purpurascens Cav in the up and down model in rats

Fundamentos: Boldoa purpurascens Cav (nitro blanco) ha sido utilizada tradicionalmente como diurética en Cuba, sin embargo, no cuenta con los estudios toxicológicos preclínicos establecidos. Objetivos: determinar la toxicidad aguda de un extracto acuoso liofilizado de hojas secas de B. purpurascens. Métodos: se realizó un estudio preclínico mediante el método de sube y baja (UDP), el grupo experimental estuvo conformado por 5 ratas hembras de la línea Sprague Dawley. Se administró una dosis límite diaria de 2 000 mg/kg. Se realizaron observaciones sistemáticas durante el transcurso del experimento y el día 14 posadministración se procedió a la eutanasia de los animales. Resultados: el peso corporal se comportó acorde a la curva de crecimiento de la especie, sin evidencia de signos tóxicos ni muerte de ningún animal. El estudio anatomopatológico macroscópico de los órganos no mostró alteraciones. Conclusiones: la dosis tóxica del extracto estudiado es superior a 2 000 mg/kg y clasifica como no tóxico(AU)

Foundations: Boldoa purpurascens Cav (nitro blanco) has been traditionally used as a diuretic in Cuba; however, the established preclinical toxicological studies have not been conducted yet. Objectives: to determine acute toxicity in a freeze-dried aqueous extract form dry leaves of B. Purpurascens. Methods: a preclinical study was undertaken by the up and down procedure. The experimental group was composed of 5 Sprague Dawley female rats. A daily limited dose of 2 000 mg/kg was administered. Systematic observations were made during the experiment and on the 14th postadministration day, the euthanasia of the animals was performed. Results: the body weight behaved according to the growth curve of the species without evidence of toxic signs or death of any animal. The macroscopic anatomopathological study of the organs showed no alterations. Conclusions: the toxic dose of the studied extract is higher than 2 000 mg/kg and classifies as non-toxic(AU)

Toxicidad aguda de un extracto acuoso de Boldoa purpurascens Cav en el modelo de sube y baja en ratas / Acute toxicity of an aqueous extract of Boldoa purpurascens Cav in the up and down model in rats

Fundamentos: Boldoa purpurascens Cav (nitro blanco) ha sido utilizada tradicionalmente como diurética en Cuba, sin embargo, no cuenta con los estudios toxicológicos preclínicos establecidos. Objetivos: determinar la toxicidad aguda de un extracto acuoso liofilizado de hojas secas de B. purpurascens. Métodos: se realizó un estudio preclínico mediante el método de sube y baja (UDP), el grupo experimental estuvo conformado por 5 ratas hembras de la línea Sprague Dawley. Se administró una dosis límite diaria de 2 000 mg/kg. Se realizaron observaciones sistemáticas durante el transcurso del experimento y el día 14 posadministración se procedió a la eutanasia de los animales. Resultados: el peso corporal se comportó acorde a la curva de crecimiento de la especie, sin evidencia de signos tóxicos ni muerte de ningún animal. El estudio anatomopatológico macroscópico de los órganos no mostró alteraciones. Conclusiones: la dosis tóxica del extracto estudiado es superior a 2 000 mg/kg y clasifica como no tóxico.

Foundations: Boldoa purpurascens Cav (nitro blanco) has been traditionally used as a diuretic in Cuba; however, the established preclinical toxicological studies have not been conducted yet. Objectives: to determine acute toxicity in a freeze-dried aqueous extract form dry leaves of B. Purpurascens. Methods: a preclinical study was undertaken by the up and down procedure. The experimental group was composed of 5 Sprague Dawley female rats. A daily limited dose of 2 000 mg/kg was administered. Systematic observations were made during the experiment and on the 14th postadministration day, the euthanasia of the animals was performed. Results: the body weight behaved according to the growth curve of the species without evidence of toxic signs or death of any animal. The macroscopic anatomopathological study of the organs showed no alterations. Conclusions: the toxic dose of the studied extract is higher than 2 000 mg/kg and classifies as non-toxic.

Actividad gastroprotectora del fruto de la musa sp abb sobre las úlceras inducidas por etanol / Gastroprotective activity of the Musa sp abb fruit on ethanol- induced stomach ulcers

La medicina natural ha ido ganando espacio en el terreno farmacológico. Al fruto de la Musa sp ABB, se le atribuye tradicionalmente la eliminación de trastornos digestivos. Comprobar experimentalmente la actividad gastroprotectora atribuida al fruto de dicha planta, para lo que se utilizó el modelo de inducción de úlceras por etanol. Se realizó el tamizaje fitoquímico, se diseñaron cinco grupos de ratas Sprague Dawley machos, se prepararon suspensiones acuosas de la cáscara y la pulpa en concentraciones de 200 mg/100 g, 300 mg/100 g y 400 mg/100 g, que fueron administradas 30 minutos antes de suministrar el agente ulcerogénico. Se cuantificaron y evaluaron las úlceras en la mucosa gástrica. Predominaron los polifenoles y los alcaloides en el análisis fitoquímico de la pulpa y la cáscara. Disminuyó significativamente el número y la severidad de las lesiones con el uso de las preparaciones empleadas, sobre todo, a partir de la cáscara. Las preparaciones de la pulpa y la cáscara del fruto de la Musa sp ABB presentan efecto gastroprotector en el modelo estudiado, lo que puede atribuirse al predominio de polifenoles y alcaloides en su composición(AU)

Introduction: Natural medicine has steadily increased its presence in pharmacology. The elimination of digestive disorders has traditionally been attributed to the fruit of the Musa sp ABB. Objective: To determine experimentally, the gastroprotective activity attributed to this fruit using the model of ethanol-induced stomach ulcer. Methods: The phytochemical sifting was carried out; five groups of male Sprague-Dawley rats were formed; aqueous suspensions from the peel and pulp of the fruit in concentrations of 200 mg/100 g, 300 mg/100 g and 400 m g/100 g were prepared. These suspensions were administered 30 minutes before the ulcerogenic agent. The ulcers in the gastric mucosa were counted and assessed: Results: In the phytochemical analysis of the pulp and peel, the polyphenols and alkaloids were predominant. There was a significant decrease in the amount and severity of the lesions after the use of the preparations, mainly the one made out of the peel. Conclusions: The preparations based on the Musa sp ABB fruit pulp and peel have a gastroprotective effect according to the model studied. This can be attributed to the predominant presence of polyphenols and alkaloids in its composition(AU)

Evaluación de la toxicidad aguda por tres métodos alternativos de 6 plantas de uso popular en Cuba / Assessment of acute toxicity by means of three alternative techniques of 6 herbs commuly used in Cuba

El MINSAP decide promover el desarrollo de formas farmacéuticas derivadas de plantas medicinales, entre ellas se encuentran el tilo, la guayaba, el orégano, la caña santa, el eucalipto y la majagua, todas las que son de amplio uso popular por propiedades como sedantes, antidiarreico, expectorante, hipotensoras, diuréticas, etc. Este trabajo se propone como objetivo general validar los métodos alternativos propuestos en las condiciones particulares de la UTEX y de manera específica: estandarizar los resultados de las tres pruebas a través de la evaluación de las 6 sustancias a ensayar y determinar la toxicidad aguda de las plantas en estudio de acuerdo a la congruencia de los resultados obtenidos(AU)