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.

Rosmarinus officinalis L. as cause of contact dermatitis

Because of the widespread use of botanicals, it has become crucial for health professionals to improve their knowledge about safety problems. Several herbal medicines contain chemicals with allergenic properties responsible for contact dermatitis. Among these, one is Rosmarinus officinalis L. (rosemary), a plant used since ancient times in folk medicine; at the present time it is used worldwide as a spice and flavouring agent, as a preservative and for medicinal and cosmetic purposes. The present article aims to revise and summarise scientific literature reporting cases of contact dermatitis caused by the use of R. officinalis as a raw material or as herbal preparations. Published case reports were researched on the following databases and search engines: PUBMED, MEDLINE, EMBASE, Google Scholar, Scopus. The used keywords were: R. officinalis and rosemary each alone or combined with the words allergy, contact dermatitis, allergic contact dermatitis, sensitisation and occupational dermatitis. The published case reports show that both rosemary extracts and raw material can be responsible for allergic contact dermatitis. Two cases related to contact dermatitis caused by cross-reactivity between rosemary and thyme were also commented. The diterpene carnosol, a chemical constituent of this plant, has been imputed as a common cause for this reaction. The incidence of contact dermatitis caused by rosemary is not common, but it could be more frequent with respect to the supposed occurrence. It seems plausible that cases of contact dermatitis caused by rosemary are more frequent with respect to the supposed occurrence, because they could be misdiagnosed. For this reason, this possibility should be carefully considered in dermatitis differential diagnosis

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Rosmarinus officinalis L. as cause of contact dermatitis.

Because of the widespread use of botanicals, it has become crucial for health professionals to improve their knowledge about safety problems. Several herbal medicines contain chemicals with allergenic properties responsible for contact dermatitis. Among these, one is Rosmarinus officinalis L. (rosemary), a plant used since ancient times in folk medicine; at the present time it is used worldwide as a spice and flavouring agent, as a preservative and for medicinal and cosmetic purposes. The present article aims to revise and summarise scientific literature reporting cases of contact dermatitis caused by the use of R. officinalis as a raw material or as herbal preparations. Published case reports were researched on the following databases and search engines: PUBMED, MEDLINE, EMBASE, Google Scholar, Scopus. The used keywords were: R. officinalis and rosemary each alone or combined with the words allergy, contact dermatitis, allergic contact dermatitis, sensitisation and occupational dermatitis. The published case reports show that both rosemary extracts and raw material can be responsible for allergic contact dermatitis. Two cases related to contact dermatitis caused by cross-reactivity between rosemary and thyme were also commented. The diterpene carnosol, a chemical constituent of this plant, has been imputed as a common cause for this reaction. The incidence of contact dermatitis caused by rosemary is not common, but it could be more frequent with respect to the supposed occurrence. It seems plausible that cases of contact dermatitis caused by rosemary are more frequent with respect to the supposed occurrence, because they could be misdiagnosed. For this reason, this possibility should be carefully considered in dermatitis differential diagnosis.

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.

Potential beneficial effects of garlic in oncohematology.

The use of non-conventional medicines, especially herbal medicine, is common in patients with cancers including haematologic malignancies. Diet components may also modify the risk of cancer through the influence on multiple processes, including DNA repair, cell proliferation and apoptosis. Garlic (Allium sativum), considered either food or herbal medicine, possesses antimutagenic and antiproliferative properties that can be used in anticancer interventions. We analyzed literature data on effects of garlic and garlic compounds which can serve as basic information to design clinical approach in oncohematology. Garlic contains water soluble and oil-soluble sulfur compounds. The latter are responsible for anticancer effects exerted through multiple mechanisms such as: inhibition of metabolic carcinogenic activation, arrest of cell cycle, antioxidant and pro-apoptotic action. Evidence about the effects of main sulfur compounds diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS), ajoene and S-allylmercaptocysteine (SAMC) in oncohematology was described. Our research highlights that data on garlic in oncohematology are essentially represented by pre-clinical studies. Although these studies must be considered as preliminary, they provided insight into biological activities of garlic compounds and support a rationale for the use of substances such as DAS, DADS, DATS and ajoene as promising anticancer agents in oncohematology.

Serotonin mediates beneficial effects of Hypericum perforatum on nicotine withdrawal signs.

Antidepressants may be effective treatment for smoking cessation and new evidence on relationship between smoking and depression is emerging. Extracts of the plant Hypericum perforatum possess antidepressant activity in humans and reduce nicotine withdrawal signs in mice. Both nicotine and H. perforatum administration elicit changes in serotonin (5-HT) formation in the brain. On this basis, we investigated the possible involvement of 5-HT in the beneficial effects of H. perforatum on nicotine withdrawal signs. With the aim to induce nicotine dependence, nicotine (2 mg/kg, four intraperitoneal injections daily) was administered for 14 days to mice (NM). Saline (controls, M) or H. perforatum extract (Ph 50, 500 mg/kg) were orally administered immediately after the last nicotine injection for 30 days after nicotine withdrawal. Another group of animals treated with nicotine (14 days) and successively with H. perforatum extract was intraperitoneally co-administered with selective 5-HT receptorial antagonist WAY 100635 (WAY) (1 mg/kg). All animals were evaluated for locomotor activity and abstinence signs, 24 after nicotine withdrawal. Brain 5-HT metabolism was evaluated in the cortex of mice sacrificed 30 days after nicotine withdrawal through evaluation of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA/5-HT ratio. After nicotine withdrawal measurement of 5-HT metabolism in the cortex showed a reduction of 5-HT content while animals treated only with Hypericum extract showed a significant reduction of total abstinence score compared to controls. WAY inhibited the reduction of total abstinence score induced by H. perforatum. Moreover, 5-HT1A expression has been evaluated 30 days after nicotine withdrawal. Our results, show a significant increase of cortical 5-HT content in NM treated with H. perforatum, with a concomitant significant increase of 5-HT1A receptor. So, it is possible to suggest an involvement of 5-HT in beneficial effects of H. perforatum on suffering produced by nicotine withdrawal in dependent mice.

Interleukin-6 involvement in antidepressant action of Hypericum perforatum.

Hypericum, a plant widely used as antidepressant has been shown to interact with the immune system. We studied the effects of the administration of the Hypericum perforatum extract Ph-50, a Hypericum extract, standardized to flavonoids (50%) and containing 0.3% of hypericin and 4.5% of hyperforin in a forced swimming test and tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) diencephalic content using a high performance liquid chromatography method in male interleukin-6 (IL-6) knock-out (IL-6(-/-)) and wild type (IL-6(+/+)) mice. Hypericum extract (Ph-50; 500 mg/kg) oral acute administration reduced the immobility time of wild type, but not of knockout mice. Tryptophan content was not modified by Hypericum in all the animal groups. Serotonin and 5-HIAA diencephalic content was increased by Hypericum in both wild type and knockout mice. However, the increase observed in the wild type was greater than in knockout mice. These data indicate that IL-6 could be necessary to the antidepressant action of Hypericum, and that this cytokine (probably) mediates the effects of Hypericum through activation of the serotonin system.

Serotonin, norepinephrine and dopamine involvement in the antidepressant action of hypericum perforatum.

Hypericum perforatum is considered an effective alternative to the synthetic antidepressants in the treatment of mild-to-moderate depression. Recently, we showed that the effects on neurotransmitter contents in different brain regions of laboratory animals are more evident after administration of hypericum extracts containing a higher concentration of flavonoids, thus suggesting that these compounds are important in the antidepressant action of hypericum perforatum. We studied the effects of Ph-50, a hypericum extract standardized to flavonoids (50%) and containing 0.3% hypericin and 4.5% hyperforin on brain serotonin content, norepinephrine and dopamine by a high-performance liquid chromatography method in discrete brain areas (cortex, diencephalon and brainstem) in male Sprague-Dawley rats. Moreover, we evaluated the effects of Ph-50 alone or in association with sulpiride (a dopamine receptor antagonist), metergoline (a serotonin receptor antagonist) and 6-hydroxydopamine (6-OH-DA, destroying norepinephrine-containing neurons) using a forced-swimming test in the rat. Hypericum extract (Ph-50; 250-500 mg/kg) with acute oral administration enhanced serotonin, norepinephrine and dopamine content in the brain and reduced the immobility time of rats in the forced-swimming test. Sulpiride, metergoline and 6-OH-DA significantly increased the period of immobility in the forced-swimming test for the rats receiving hypericum extract (Ph-50). The results indicate that the neurotransmitters studied could be involved in the anti-immobility effects of hypericum, and suggest that its antidepressant action is probably mediated by serotonergic, noradrenergic and dopaminergic system activation.

The phytoestrogen alpha-zearalenol reverses endothelial dysfunction induced by oophorectomy in rats.

It has been shown recently that alpha-zearalenol, a resorcyclic acid lactone, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dysfunction induced by estrogen deficiency in rats. Female mature Sprague-Dawley rats underwent a bilateral oophorectomy (OVX rats). Sham-operated animals (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: alpha-zearalenol (1 mg/kg/day, i.m., for 4 weeks), 17beta-estradiol (20 microg/kg/day, i.m., for 4 weeks), or their vehicle (100 microl, i.m., of cottonseed oil). Two other groups of rats were treated with alpha-zearalenol or 17beta-estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, i.m., for 4 weeks). Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, and plasma alpha-zearalenol were studied. We also investigated endothelial-dependent (acetylcholine, 10 nM to 10 microM) and endothelial-independent (sodium nitroprusside, 15 nM to 30 nM) relaxation of aortic rings, as well as N(G)-methyl-L-arginine (L-NMA: 10 to 100 microM)-induced vasoconstriction and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR, and plasma cholesterol. In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 +/- 0.5 pg/ml; sham OVX, 35 +/- 6 pg/ml), impaired endothelial-dependent relaxation and blunted L-NMA-induced contraction (L-NMA 100 microM: sham OVX, 2.7 +/- 0.3 g/mg tissue; OVX, 1.3 +/- 0.1 g/mg tissue). Moreover OVX rats showed a reduced calcium-dependent NO synthase (cNOS) activity. Treatment with alpha-zearalenol or with 17beta-estradiol reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. These effects were abolished by the pure estrogen receptor antagonist ICI 182780. Our data suggest that alpha-zearalenol improves endothelial-dependent relaxation in OVX rats through an estrogen receptor-mediated effect.

Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis.

We studied the effects of pre-treatment (15 days) with oral administration of Ginkgo biloba extract (Ph-Gb 37.5-150 mg/kg) on brain malonildialdehyde (MDA), brain edema, brain nitrite and nitrate and delayed neuronal death following transient cerebral ischemia in the Mongolian gerbil. Survival was not modified, however, pre-treatment with Ginkgo biloba significantly and in a dose-dependent way reduced post-ischemic brain MDA levels and post-ischemic brain edema. Delayed neuronal death in the CA1 of the hippocampus was attenuated by the highest dose of the extract. Increase of nitrite and nitrate was observed after cerebral ischemia in the hippocampus and it was dose-dependently reduced in animals pretreated with Ph-Gb, thus suggesting that neuroprotective effects of Ginkgo biloba may be due to an inhibitory action on nitric oxide formation.

Effects of Hypericum perforatum on levels of 5-hydroxytryptamine, noradrenaline and dopamine in the cortex, diencephalon and brainstem of the rat.

The plant Hypericum perforatum is used in folk medicine to treat several diseases and research attention has been recently focused on its antidepressant action. Hypericin and flavonoids are the most important constituents of the plant, but the exact role of these compounds in the effects of hypericum on mood disorders is not well known. We have investigated the contribution of these compounds to the antidepressant effects of hypericum. The effects of acute administration of hypericum extracts on levels of 5-hydroxytryptamine (5-HT), tryptophan, 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline and dopamine in the cortex, diencephalon and brainstem was evaluated. The levels of these neurotransmitters were measured 1 h and 24 h after administration of two different extracts, one containing 0.3% hypericin and 6% flavonoids (Li 160; 25-500 mgkg(-1)), the other containing 0.3% hypericin and 50% flavonoids (Ph-50; 25-500 mgkg(-1)). Results from experiments performed on 5-HT turnover were compared with the effects of fluoxetine (10-80 mgkg(-1)). Li 160, Ph-50 and fluoxetine induced a significant increase in the 5-HT content of the cortex. In the diencephalon Ph-50, but not Li 160 or fluoxetine, elicited an increase in 5-HT and 5-HIAA levels. In the brainstem Ph-50 and fluoxetine caused an increase in 5-HT content; Li 160 did not change neurotransmitter content. Both Li 160 and Ph-50 caused increases of noradrenaline and dopamine in the diencephalon. In the brainstem only Ph-50 induced an increase in noradrenaline content. Our data confirm that acute administration of hypericum extracts modifies the levels of neurotransmitters involved in the pathophysiology of mood disorders. When the extracts contain a higher concentration of flavonoids the effects are more widespread and involve brain regions such as diencephalon and brainstem that are implicated in depression.