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.

Interleukin 31 is involved in intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder characterized by maternal itching and altered liver function. Interleukin (IL)-31 is known to be involved in the pathogenesis of pruritic inflammatory skin diseases. In a three-year period, 13 women with a singleton pregnancy and a diagnosis of intrahepatic cholestasis (ICP) were enrolled together with 26 healthy single pregnant women who concluded an uncomplicated pregnancy. The inclusion criteria were itching and elevated levels of liver transaminases. Median serum levels of IL-31 were significantly higher in ICP patients than in the control group (p = 0.004). Furthermore, IL-31 values were directly dependent on liver transaminase levels.

Gait analysis in children with haemophilia: first Italian experience at the Turin Haemophilia Centre.

AIM: To investigate the functional status in haemophilia patients referred to an Italian paediatric haemophilia centre using gait analysis, verifying any differences between mild, moderate or severe haemophilia at a functional level. METHODS: Forty-two patients (age 4-18) presenting to the Turin Paediatric Haemophilia Centre who could walk independently were included. Therapy included prophylaxis (n = 21), on-demand (n = 17) or immune tolerance induction + inhibitor (n = 4). Patients performed a test of gait analysis. Temporal, spatial and kinematic parameters were calculated for patient subgroups by disease severity and background treatment, and compared with normal values. RESULTS: Moderate (35.7%) or severe (64.3%) haemophilia patients showed obvious variations from normal across a variety of temporal and spatial gait analysis parameters, including step speed and length, double support, swing phase, load asymmetry, stance phase, swing phase and speed. Kinematic parameters were characterized by frequent foot external rotation with deficient plantar flexion during the stance phase, retropelvic tilt, impaired power generation distally and reduced ground reaction forces. Both Gait Deviation Index and Gait Profile Score values for severe haemophilia patients indicated abnormal gait parameters, which were worst in patients with a history of past or current use of inhibitors and those receiving on-demand therapy. CONCLUSION: Functional evaluation identified changes in gait pattern in patients with severe and moderate haemophilia, compared with normal values. Gait analysis may be a useful tool to facilitate early diagnosis of joint damage, prevent haemophilic arthropathy, design a personalized rehabilitative treatment and monitor functional status over time.

IL-31 and IL-33 circulating levels in allergic contact dermatitis.

Enhanced IL-31 expression in skin biopsies is present in allergic contact dermatitis (ACD). IL-33 expression is induced in keratinocytes and in skin of ACD patients. This overexpression is present in both allergic and irritant conditions. The aim of this work was to test the systemic involvement of IL-31 and IL-33 in ACD. IL-31 levels were significantly higher in patients than in controls. IL-33 serum levels, on the contrary, were similar in patients and controls. This work shows a possible systemic involvement of IL-31 and the absence of a systemic involvement of IL-33 in ACD. IL-31 levels do not seem related to the allergen involved, and did not change on the strength of the allergen involved. More likely, IL-31 levels are related to the itch. IL-33, instead, is secreted from damaged or inflamed tissue and might function as an early warning system at the site of skin damage. In the future, IL-31 could be a possible therapeutic target of all pruritic skin diseases resistant to conventional therapies.

Oral adverse reactions due to cinnamon-flavoured chewing gums consumption.

Cinnamon-flavoured products (toothpaste, chewing gum, food, candy and mouthwash) can cause oral adverse reactions; among these, the most common is contact stomatitis (cinnamon contact stomatitis, CCS). Signs and symptoms of contact allergic reactions affecting the oral mucosa can mimic other common oral disorders, making diagnosis difficult. As CCS may be more prevalent than believed and its clinical features can frequently determine misdiagnosis, we reviewed case reports and case series of oral adverse reactions due to cinnamon-containing chewing gums, emphasizing clinical aspects, diagnostic and management procedures. We also proposed an algorithm to perform a diagnosis of CCS as in the previous published literature the diagnostic approach was not based on a harmonized and shared evidence-based procedure. Moreover, as patients can refer to different specialists as dentists, dermatologists and allergists, a multidisciplinary approach is suggested.

Systemic nickel allergy: oral desensitization and possible role of cytokines interleukins 2 and 10.

Nickel ingested with food can elicit either systemic cutaneous or gastrointestinal symptoms causing a systemic nickel allergy syndrome (SNAS) that can be treated with tolerance by oral ingestion of the metal. It has been suggested that interleukins 2 (IL-2) and 10 (IL-10) are involved in the mechanisms underlying oral tolerance. We evaluated the clinical efficacy of oral desensitization therapy in SNAS consisting in the administration of nickel sulphate. Because nickel allergy prevalently affects women, only female subjects (N = 22) were recruited. Oral nickel desensitizing therapy was associated with low-nickel diet for three months. Before and after therapy, clinical conditions were evaluated, and circulating cytokines IL-2 and IL-10 were measured. After the two-year treatment, visual analogue scale (VAS) scores for symptoms were significantly reduced (P less than 0.001). Patients were released by either cutaneous or gastrointestinal symptoms and by tolerating nickel-containing food. At the end of the treatment, nickel oral challenge test was negative in 18 patients, and IL-2 level in the serum was significantly reduced while IL-10 was increased, although this datum was not statistically significant. Our study confirms the clinical efficacy of nickel oral immunotherapy and focuses on the mechanisms triggered by oral tolerance indicating that reduction of IL-2 can be associated with success of oral nickel desensitizing therapy.

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.

Splenic infarcts in chronic hepatopathy accompanied by cryoglobulinemia: two case reports.

Splenic infarct is a rare condition often related to haematological, cardiovascular, autoimmune or infectious diseases diagnosed with increasing frequency due to the large use of abdominal imaging techniques. Cryoglobulins are serum proteins that reversibly precipitate at low temperatures, small vessels vasculitis represent their most common clinical manifestation and are often associated with chronic liver disorders or with lymphoproliferative diseases. Here the authors report the cases of two patients, both affected by chronic liver disease associated with cryoglobulinemia, admitted to our unit for an on-going active infectious disease (without signs of endocarditis) who presented multiple splenic infarcts as an unexpected complication. The authors hypotize that in both cases splenic infarct may be related not only to a thrombogenic state or to splenic vasculitis but also to other immuno-mediate mechanism related to cryoglobulins synthesis and clearance.

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.

Enzymatic urea adaptation: lactate and malate dehydrogenase in elasmobranchs.

Lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) electrophoretic tissue patterns of two different orders of Elasmobranchii: Carchariniformes (Galeus melanostomus and Prionace glauca) and Squaliformes (Etmopterus spinax and Scymnorinus licha) were studied. The number of loci expressed for these enzymes was the same of other elasmobranch species. Differences in tissue distribution were noted in LDH from G. melanostomus due to the presence of an additional heterotetramer in the eye tissue. There were also differences in MDH. In fact, all the tissues of E. spinax and G. melanostomus showed two mitochondrial bands. Major differences were noted in the number of isozymes detected in the four compared elasmobranchs. The highest polymorphism was observed in E. spinax and G. melanostomus, two species that live in changeable environmental conditions. The resistance of isozymes after urea treatment was examined; the resulting patterns showed a quite good resistance of the enzymes, higher for LDH than MDH, also at urea concentration much greater than physiological one. These results indicated that the total isozyme resistance can be considered higher in urea accumulators (such as elasmobranchs) than in the non-accumulators (such as teleosts).

Synthesis, characterization, and analytical studies of adosupine, a potential new drug for urinary incontinence.

The synthesis and the spectroscopic characterization of a new potential drug for urinary incontinence, adosupine, is described. Adosupine and its potential synthesis impurities were analyzed by a new HPLC method that was developed with a C18 reversed-phase column. The analysis was made under isocratic conditions, with a mobile phase of acetonitrile:water (15:85, v/v). Resolution of all synthesis impurities was allowed. The method was also applied to stability studies of adosupine in solid state and in solution under different conditions. With the conditions used, only one degradation product was shown by HPLC analysis; it was isolated, characterized, and identified as the hydrolysis product of the lactam ring present in the adosupine structure.

High-performance liquid chromatographic method for assay of otilonium bromide, diazepam, and related compounds in finished pharmaceutical forms.

A rapid, simple, stability-indicating assay procedure for otilonium bromide, a smooth muscle relaxant agent, and diazepam in composite tablet analysis was developed with high-performance liquid chromatography. The tablet matrix was dissolved with water, and drugs were extracted with acetonitrile containing an internal standard. An aliquot was centrifuged and chromatographed on a 5-microns, reversed-phase column with 0.5 M sodium acetate trihydrate buffer containing 5 mM 1-heptanesulfonic acid monohydrate sodium salt:methanol (30:70; v/v; adjusted to pH 6.0 with glacial acetic acid) as the mobile phase. The selectivity of the chromatographic system was demonstrated by resolving both compounds from various potential degradation products of each compound. The method is linear, quantitative, and reproducible.

Rapid simultaneous determination of tryptophan and tyrosine in synthetic peptides by derivative spectroscopy.

A method for the simultaneous quantitative determination of tryptophan and tyrosine in synthetic peptides by second-order derivative diode-array spectroscopy is reported. The method does not require hydrolysis of the peptides or a derivatization reaction; the sample is dissolved in 0.1 N NaOH and directly scanned between 262 and 264 nm to detect tyrosine and between 304 and 306 nm to detect tryptophan. From these results the peptide content of the synthetic sample can be easily calculated in a very simple and fast way. The results obtained by the described method with several peptides are compared with those obtained by classical high-performance liquid chromatographic analysis of amino acids after peptide hydrolysis. A very good correlation was found both for the tryptophan/tyrosine molar ratio and the peptide content.

Simultaneous determination of otilonium bromide and diazepam by first-derivative spectroscopy.

A rapid, simple assay procedure was developed for simultaneous analysis of otilonium bromide, a smooth-muscle relaxant, and diazepam in tablets containing 20 mg of otilonium bromide and 2 mg of diazepam (20:2 tablets) or 40 mg of otilonium bromide and 2 mg of diazepam (40:2 tablets) by "zero-crossing" first-derivative spectroscopy. The tablets were dissolved in 0.01 N HCl, mixtures were centrifuged at 3500 rpm (2472 x g) for 5 min, and first-derivative spectra were recorded. The absolute values of the derivative were measured at 264 nm for determination of otilonium bromide and between 406 and 408 nm (380 nm for analysis of 40:2 tablets) for determination of diazepam. The method is linear, quantitative, and reproducible and can also be used for the tablet dissolution test. Ten tablets of the same batch were analyzed by the described method and by a high-performance liquid chromatographic method, and the results were in good agreement.

High-performance liquid chromatographic method for determination of ronactolol in urine and plasma: evaluation of pharmacokinetic parameters in healthy humans.

Ronactolol [(+/-)-4'-[2-hydroxy-3-(isopropylamino)propoxy]-p-anisanilide], a new aminopropanol derivative showing beta-adrenoreceptor blocking activity, was administered orally as capsules to healthy humans at three single doses (30, 60, and 120 mg). Two HPLC methods were developed separately for determination of drug levels in urine and plasma. For plasma samples, after addition of internal standard (IS), a single-step extraction of alkalinized plasma was performed with methylene chloride. The organic layer was evaporated to dryness under reduced pressure, and the residue was taken up and chromatographed on a microbore silica column. Ronactolol and IS were detected by a UV detector at a wavelength of 278 nm. Excellent linearity was observed between the peak height ratios (ronactolol:IS) and concentrations in plasma. The lowest limit of detection (signal:noise, 3:1) was 1.5 ng/mL of plasma. Urine samples were directly injected and chromatographed on a microbore C18 column with an ion-pairing mobile phase. Excellent linearity was observed between the peak areas and concentrations in urine. The lowest limit of detection (signal:noise, 3:1) was 75 ng/mL of urine. The assay was used to determine the main pharmacokinetic parameters in healthy humans.

Analysis of platelet-activating factor by gas chromatography-mass spectrometry: low-energy electron impact of the corresponding 3-acetyl-2-tert.-butyldimethylsilyl derivative.

A method for the analysis of platelet-activating factor in platelets employing gas chromatography and selected-ion monitoring mass spectrometry with low-energy electron impact and stable isotope dilution was developed. The procedure involved Bligh and Dyer extraction of the sample followed by thin-layer chromatographic purification. Platelet-activating factor is successively hydrolysed to the corresponding 2-acetyl-1-O-alkylglycerol by digestion with phospholipase C, and the product is allowed to isomerize to the more thermodynamically stable 3-acetyl-1-O-alkylglycerol before column purification and derivatization of the free OH with tert.-butyldimethylchlorosaline-imidazole. This reagent is of common use in platelet-activating factor derivatization, but is made to react with 2-acetyl instead of 3-acetyl isomer. The advantages of using the latter for the final derivatization are discussed and this method is compared with others currently available for gas chromatographic-mass spectrometric analysis of platelet-activating factor.

Gas chromatographic-mass spectrometric determination of two new antimycotic agents, 1-[(5-chloro-2-benzofuranyl)(2-chlorophenyl)methyl]-1H-imidazole and 1-[(5-bromo-2-benzofuranyl)phenylmethyl]-1H-imidazole, in rabbit plasma following topical administration: a preliminary comparison with bifonazole.

A method for the analysis of the antimycotic drugs 1-[(5-chloro-2-benzofuranyl)(2-chlorophenyl)methyl]-1H-imidazole, 1-[(5-bromo-2-benzofuranyl)phenylmethyl]-1H-imidazole and bifonazole in rabbit plasma, employing gas chromatography-mass spectrometry with selected-ion monitoring, was developed. The procedure involved single-step purification of the biological matrix via liquid-liquid extraction on Extrelut columns and use of a carrier substance to minimize the negative effects of adsorption sites during the gas chromatographic process. The limits of detection ranged from 0.1 to 1.4 ng/ml, starting from a 200-microliter sample. The method was applied to a preliminary evaluation of percutaneous absorption of both drugs in the rabbit after a single administration, in comparison with bifonazole.

Study on the absorption of ketoprofen topically administered in man: comparison between tissue and plasma levels.

In this study the transcutaneous passage of ketoprofen (gel) topically administered and its distribution in the inner part of the knee-joint were evaluated in six patients. The ketoprofen concentrations detected were: 4.70 mcg/g +/- 3.87 in the intra-articular adipose tissue; 2.35 mcg/g +/- 2.41 in the capsular sample and 1.31 mcg/g +/- 0.89 in the synovial fluid. Plasma concentrations of the drug were also examined. In the samples studied, the ketoprofen levels amounted to about one hundred times higher than the plasma concentrations.