Vigilance on use of drugs, herbal products, and food supplements during pregnancy: focus on fosfomycin.

PURPOSE: Urinary tract infection (UTI) is defined as a common bacterial infection that can lead to significant morbidity such as stricture, fistula, abscess formation, bacteremia, sepsis, pyelonephritis, and kidney dysfunction with a mortality rates reported of 1% in men and 3% in women because of development of pyelonephritis. UTIs are more common in women and the 33% of them require antimicrobials treatment for at least one episode by the age of 24 years. UTIs are the most common infections observed during pregnancy and up to 30% of mothers with not treated asymptomatic bacteriuria may develop acute pyelonephritis which consequently can be associated to adverse maternal and fetal outcomes. All bacteriuria in pregnancy should be treated with antimicrobial treatments being safe for both the mother and the fetus. Approximately one every four women receives prescription of antibiotic treatment during pregnancy, nearly 80% of all the prescription medications during gestation. The use of fosfomycin to treat cystitis in pregnancy generally considered safe and effective. Even though use on antibiotics for urinary tract infections is considered generally safe for the fetus and mothers, this opinion is not based on specific studies monitoring the relationship of among urinary infections, consumption of antibiotics, and pregnancy outcomes. MATERIALS AND METHODS: On this basis we decided to analyze data from the database of our multicenter study PHYTOVIGGEST, reporting data from 5362 pregnancies, focusing on use of fosfomycin. Principal outcomes of pregnancy in women treated with fosfomycin were taken into consideration. RESULTS: Women who have been treated with urinary antibiotics during the pregnancy were 183. With respect to the total number of pregnancies of our sample, these women represented the percentage of 3.49% (187/5362). Analysis of different outcomes of pregnancy such as gestational age, neonatal weight, and neonatal Apgar index did not show any significant difference. At the same time, analysis of data of pregnancy complicancies (such as urgent cesarean delivery, use of general anesthesia, need to induce labor) did not show any difference in women taking fosfomycin during pregnancy and those not taking it. CONCLUSIONS: Our data, based on a large number of pregnancies, confirm the safety use of fosfomycin use in pregnancy.

Melatonin treatment suppresses appetite genes and improves adipose tissue plasticity in diet-induced obese zebrafish.

PURPOSE: Overweight and obesity are important risk factors for diabetes, cardiovascular diseases, and premature death in modern society. Recently, numerous natural and synthetic compounds have been tested in diet-induced obese animal models, to counteract obesity. Melatonin is a circadian hormone, produced by pineal gland and extra-pineal sources, involved in processes which have in common a rhythmic expression. In teleost, it can control energy balance by activating or inhibiting appetite-related peptides. The study aims at testing effects of melatonin administration to control-fed and overfed zebrafish, in terms of expression levels of orexigenic (Ghrelin, orexin, NPY) and anorexigenic (leptin, POMC) genes expression and morphometry of visceral and subcutaneous fat depots. METHODS: Adult male zebrafish (n = 56) were divided into four dietary groups: control, overfed, control + melatonin, overfed + melatonin. The treatment lasted 5 weeks and BMI levels of every fish were measured each week. After this period fishes were sacrificed; morphological and morphometric studies have been carried out on histological sections of adipose tissue and adipocytes. Moreover, whole zebrafish brain and intestine were used for qRT-PCR. RESULTS: Our results demonstrate that melatonin supplementation may have an effect in mobilizing fat stores, in increasing basal metabolism and thus in preventing further excess fat accumulation. Melatonin stimulates the anorexigenic and inhibit the orexigenic signals. CONCLUSIONS: It seems that adequate melatonin treatment exerts anti-obesity protective effects, also in a diet-induced obesity zebrafish model, that might be the result of the restoration of many factors: the final endpoint reached is weight loss and stabilization of weight gain.

Effect of Citrus bergamia juice on human neuroblastoma cells in vitro and in metastatic xenograft models.

Neuroblastoma is the most common extracranial pediatric solid tumor with poor prognosis in children with disseminated stage of disease. A number of studies show that molecules largely distributed in commonly consumed fruits and vegetables may have anti-tumor activity. In this study we evaluate the effect of Citrus bergamia (bergamot) juice (BJ) in vitro and in a spontaneous metastatic neuroblastoma SCID mouse model. Qualitative and quantitative characterizations of BJ flavonoid fractions were performed by RP-HPLC/PDA/MS. We show that BJ significantly affects SK-N-SH and LAN-1 cell proliferation in vitro, but fails to reduce primary tumor weight in vivo. Moreover, BJ reduced cell adhesiveness and invasion of LAN-1 and SK-N-SH cells in vitro and the number of pulmonary metastases under consideration of the number of tumor cells in the blood in mice inoculated with LAN-1 cells in vivo. These effects without any apparent sign of systemic toxicity confirm the potential clinical interest of BJ and lay the basis for further investigation in cancer.

Cooperation of histone deacetylase inhibitors SAHA and valproic acid in promoting sodium/iodide symporter expression and function in rat Leydig testicular carcinoma cells.

The presence of the sodium/iodide symporter (NIS) is the prerequisite for the use of the radioiodine in the treatment of thyroid cancer. Thus, stimulators of NIS expression and function are currently investigated in cellular models of various human malignancies, also including extrathyroid cancers. In this study, we analyzed the effects of the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), on NIS expression and function in rat Leydig testicular carcinoma cells (LC540). LC540 cells were exposed to SAHA 3 µM and VPA 3 mM (alone and in combination), and cell viability evaluated by MTT assay and cell counting, NIS mRNA and protein levels by using, respectively, real-time RT-PCR and western blotting. NIS function was evaluated by iodide uptake assay. We found that both HDACi were able to stimulate the transcription of NIS gene, but not its protein expression, while the association of SAHA and VPA increased both NIS transcript and protein levels, resulting in significant sixfold enhancement of radioiodine uptake capacity of LC540 cells. These data demonstrate the presence of an epigenetic control of NIS expression in Leydig tumor cells, suggesting the possibility to use the combination of these two HDACi for a radioiodine-based treatment of these malignancies.

Passiflora incarnata L.: ethnopharmacology, clinical application, safety and evaluation of clinical trials.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Passiflora incarnata Linnaeus comprises approximately 520 species belonging to the Passifloraceae family. The majority of these species are vines found in Central or South America, with rare occurrence in North America, Southeast Asia and Australia. The genus Passiflora incarnata has long been used in traditional herbal medicine for the treatment of insomnia and anxiety in Europe, and it has been used as a sedative tea in North America. Furthermore, this plant has been used for analgesic, anti-spasmodic, anti-asthmatic, wormicidal and sedative purposes in Brazil; as a sedative and narcotic in Iraq; and for the treatment of disorders such as dysmenorrhoea, epilepsy, insomnia, neurosis and neuralgia in Turkey. In Poland, this plant has been used to treat hysteria and neurasthenia; in America, it has been used to treat diarrhoea, dysmenorrhoea, neuralgia, burns, haemorrhoids and insomnia. Passiflora incarnata L. has also been used to cure subjects affected by opiate dependence in India. This review aims to provide up-to-date information about the pharmacology, clinical efficacy and clinical safety of Passiflora incarnata L. based on the scientific literature. In particular, the methodological accuracy of clinical trials is analysed in accordance with current consolidated guidelines on reporting the clinical efficacy of herbal medicine, offering new insight into opportunities for future research and development. METHODS: A bibliographic investigation was performed by examining the available data on Passiflora incarnata L. from globally accepted scientific databases and search engines (Pubmed, Scopus and Web of Science, SciFinder and Google Scholar). We selected studies, case reports, and reviews addressing the pharmacology and safety of Passiflora incarnata. RESULTS: Although numerous Passiflora incarnata L. derivative products have been commercialised as alternative anxiolytic and sedative remedies based on their long tradition of use, their supposed efficacy does not appear to be adequately corroborated by the literature, with clinical studies often featuring inadequate methodologies and descriptions of the products under investigation. This medicinal plant has shown a wide spectrum of pharmacological activities in preclinical experiments, including anxiolytic, sedative, antitussive, antiasthmatic, and antidiabetic activities. The plant has a good safety profile. The clinical trials that we included in this review were designed to evaluate and in some cases confirm promising observations of preclinical pharmacological activity, and the methodological limits of these studies are characterised here. CONCLUSION: In conclusion, clinical studies on the effects of products containing herbal preparations based on Passiflora incarnata reveal crucial weaknesses such as poor details regarding the drug extract ratio, limited patient samples, no description of blinding and randomisation procedures, incorrect definition of placebo, and lack of intention to treat analysis. In conclusion, the results of this review suggest that new clinical trials should be conducted using a more rigorous methodology to assess the traditional putative efficacy of Passiflora incarnata L.

Serotonin involvement in Rhodiola rosea attenuation of nicotine withdrawal signs in rats.

Rhodiola rosea has been used for centuries in the traditional medicine to stimulate nervous system, to enhance physical and mental performance and to treat fatigue. It is known that administration of Rhodiola rosea extract elicits antidepressant activity, but the mechanism of action still remains unclear. Evidence from animal models and human studies show that nicotine reduces symptoms of depression and that nicotine cessation induces depressive-like symptoms. We investigated the effects of Rhodiola rosea on nicotine withdrawal signs. Nicotine dependence was induced by subcutaneous nicotine injection (2 mg/kg, four times daily) for 14 days. Another group of animals treated with nicotine (for 14 days) and successively with Rhodiola rosea extract was co-administered with selective 5-HT receptorial antagonist WAY 100635 (1 mg/kg). After nicotine withdrawal animals were evaluated for behavioural parameters (locomotor activity, abstinence signs, marble burying test), diencephalic serotonin metabolism and serotonin receptor-1A expression. Results show a significant increase of 5-HT content in N treated with R. rosea, with a significant increase of serotonin receptor 1A, suggesting an involvement of serotonin in beneficial effects of R. rosea on suffering produced by nicotine withdrawal.

Cell signaling pathways in the mechanisms of neuroprotection afforded by bergamot essential oil against NMDA-induced cell death in vitro.

BACKGROUND AND PURPOSE: The effects of bergamot essential oil (BEO; Citrus bergamia, Risso) on excitotoxic neuronal damage was investigated in vitro. EXPERIMENTAL APPROACH: The study was performed in human SH-SY5Y neuroblastoma cells exposed to N-methyl-D-aspartate (NMDA). Cell viability was measured by dye exclusion. Reactive oxygen species (ROS) and caspase-3 activity were measured fluorimetrically. Calpain I activity and the activation (phosphorylation) of Akt and glycogen synthase kinase-3beta (GSK-3beta) were assayed by Western blotting. KEY RESULTS: NMDA induced concentration-dependent, receptor-mediated, death of SH-SY5Y cells, ranging from 11 to 25% (0.25-5 mM). Cell death induced by 1 mM NMDA (21%) was preceded by a significant accumulation of intracellular ROS and by a rapid activation of the calcium-activated protease calpain I. In addition, NMDA caused a rapid deactivation of Akt kinase and this preceded the detrimental activation of the downstream kinase, GSK-3beta. BEO (0.0005-0.01%) concentration dependently reduced death of SH-SY5Y cells caused by 1 mM NMDA. In addition to preventing ROS accumulation and activation of calpain, BEO (0.01%) counteracted the deactivation of Akt and the consequent activation of GSK-3beta, induced by NMDA. Results obtained by using specific fractions of BEO, suggested that monoterpene hydrocarbons were responsible for neuroprotection afforded by BEO against NMDA-induced cell death. CONCLUSIONS AND IMPLICATIONS: Our data demonstrate that BEO reduces neuronal damage caused in vitro by excitotoxic stimuli and that this neuroprotection was associated with prevention of injury-induced engagement of critical death pathways.