Enrica Cecchi

Use, Attitudes and Knowledge of Complementary and Alternative Drugs (CADs) Among Pregnant Women: a Preliminary Survey in Tuscany.

To explore pregnant womens use, attitudes, knowledge and beliefs of complementary and alternative drugs (CADs) defined as products manufactured from herbs or with a natural origin. A preliminary survey was conducted among 172 pregnant women in their third trimester of pregnancy, consecutively recruited in two obstetrical settings; 15 women were randomly selected to compute a test-to-retest analysis. Response rate was 87.2%. Test-to-retest analysis showed a questionnaires reproducibility exceeding a K-value of 0.7 for all items. Mean age was 32.4 ± 0.4 years; most women were nulliparae (62.7%). The majority of subjects (68%) declared to have used one or more CADs during their lifetime; 48% of pregnant women reported taking at least one CAD previously and during the current pregnancy. Womens habitual use of CADs meant they were at higher risk of taking CADs also during pregnancy (adjusted odds ratio = 10.8; 95% confidence interval: 4.7–25.0). Moreover, 59.1% of the subjects were unable to correctly identify the type of CADs they were using. The majority of women resorted to gynecologists as the primary information source for CADs during pregnancy, while they mainly referred to herbalists when not pregnant. Habitual use of CADs seems to be a strong predictor for their ingestion also during pregnancy; in addition most subjects were unable to correctly identify the products they were taking. In the light of the scanty data concerning the safety of CADs during pregnancy, these preliminary results confirm the need to investigate thoroughly the situation of pregnant women and CADs consumption.

Lack of nitric oxide‐ and guanosine 3′:5′‐cyclic monophosphate‐dependent regulation of α‐thrombin‐induced calcium transient in endothelial cells of spontaneously hypertensive rat hearts

While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca2+]i) is still unknown. Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains. Measuring [Ca2+]i by imaging analysis of fura‐2‐loaded cells, we demonstrated that α‐thrombin (3−180 U l−1) induced a superimposable dose‐dependent calcium transient in ECs from both strains. In WKY ECs, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP) dose‐dependently (10–100 μM) and 0.1 μM atrial natriuretic factor (ANF) reduced the maximum and the decay time of α‐thrombin‐induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP‐dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of α‐thrombin‐induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ineffective. SNAP (100 μM) and 0.1 μM ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively. In SHR ECs, α‐thrombin‐induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100 μM) and 0.1 μM ANF increased cyclic GMP content up to 9.3 and 51 fold respectively. In WKY ECs, SNAP dose‐dependently (10–100 μM) reduced also bradykinin‐induced calcium transient, while in SHR ECs was ineffective. We concluded that in SHR ECs, the cyclic GMP‐dependent regulation of calcium transient is lost.

Association of serum creatinine and age with headache caused by nitrates

To assess whether serum creatinine and age are associated with headache induced by nitrates, 2742 hospitalized patients taking nitrates were studied during their hospital stay. Those patients with admission serum creatinine levels from 97 to 133 μmol/L and >133 μmol/L were compared with patients with creatinine levels < 97 μmol/L. Gender, body mass index, comorbidity, cognitive status, new intake of nitrates, number of daily administrations, and daily dosage, as well as intake of angiotensin converting enzyme inhibitors, calcium antagonists, diuretics and nonsteroidal anti‐inflammatory drugs were examined as possible confounders. Fifty‐six patients had headaches that had a causal link with intake of nitrates. Compared with the lowest creatinine group, after adjustment for potential confounding variables, the odds ratios and 95% confidence interval (95% CI) for headache caused by nitrates associated with increasing serum creatinine levels were 0.6 (95% CI, 0.3 to 1.1) and 0.2 (95% CI, 0.0 to 1.2), respectively (p for trend = 0.013). Increasing age was inversely associated with headache (odds ratio for 10‐year increase, 0.6 [95% CI, 0.5 to 0.7]). Serum creatinine and age were independently and inversely associated with headache caused by nitrates.

Effect of some cyclooxygenase inhibitors on the increase in guanosine 3':5'-cyclic monophosphate induced by NO-donors in human whole platelets.

The effect of the NSAIDs indomethacin, indoprofen, diclofenac and acetylsalicylic acid on the increase in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) induced by nitric oxide‐donor agents was tested in human whole platelets and in platelet crude homogenate. In whole platelets, indomethacin reduced the increase in cyclic GMP induced by the nitric oxide‐donors (NO‐donors) sodium nitroprusside (NaNP) and S‐nitroso‐N‐acetylpenicillamine (SNAP) in a dose‐dependent way, its IC50 being 13.7 μm and 15.8 μm, respectively. Of the other cyclooxygenase inhibitors tested, only indoprofen reduced the increase in cyclic GMP induced by both NO‐donors in a dose‐dependent way (IC50=32.7 μm, NaNP and 25.0 μm, SNAP), while acetylsalicylic acid (up to 1000 μm) and diclofenac (up to 100 μm) were ineffective. However, in platelet crude homogenate neither indomethacin nor indoprofen reduced the cyclic GMP production. Indomethacin (10 μm), indoprofen (30 μm), diclofenac (100 μm) and acetylsalicylic acid (1000 μm) showed a comparable efficacy in inhibiting platelet thromboxane B2 (TXB2) production, suggesting that the inhibitory effect of indomethacin and indoprofen on the increase in cyclic GMP induced by both NO‐donors was not mediated by inhibition of cyclooxygenase. In vitro, the NSAIDs analysed did not interfere with nitrite production of SNAP. The unhomogeneous behaviour of NSAIDs on the increase in cyclic GMP induced by NO‐donors in whole platelets may contribute to the different pharmacological and toxicological characteristics of the drugs, providing new knowledge on the effect of indomethacin and indoprofen.

Increased levels of CA 125 and CA 19·9 serum tumour markers following cyclic combined hormone replacement therapy

We report a case of increase in serum tumour markers CA 125 and CA 19·9 induced by cyclic combined hormone replacement therapy (HRT). A 52‐year‐old Caucasian post‐menopausal woman presented with a slight enlargement of the right ovary and uterine fibromyomatosis. She was taking HRT for 4 years in a cyclic combined regimen of 2 mg oestradiol with 1 mg cyproterone acetate. The serum tumour markers occasionally measured were in normal range except CA 19·9 (997 U/mL; normal values 0·0–37) and CA 125 (85 U/mL; normal values 0·0–35). However, on one occasion, the CA 19·9 and CA 125 were high and then showed persistently high values (1005 and 81·3 U/mL, respectively). Radiodiagnostic investigations excluded any malignancies and a hysteroscopy showed endometrial thickening. After discontinuation of HRT, CA 125 levels returned to normal after 1 month, whereas CA 19·9 took 6 months to do so. Four months after the beginning subsequent therapy with over‐the‐counter phyto‐oestrogens a new serum test showed an increase in CA 19·9 but CA 125 remained within the normal range. Phyto‐oestrogen therapy was then interrupted and 1 month later CA 19·9 returned to normal. In this case, cyclic HRT was the probable cause of CA 19·9 and CA 125 increase. Positive dechallenge and subsequent CA 19·9 increase after phyto‐oestrogen intake seem to confirm the role of oestrogens as the cause of the endometrial thickening through hormonal imbalance. Increased CA 19·9 and CA 125 levels in benign gynaecological conditions may be a source of misdiagnosis of malignant disease.

Does Aspirin Attenuate the Beneficial Effect of ACE Inhibitors in Elderly People with Heart Failure

BackgroundSeveral studies have raised concerns over a possible reduction in the beneficial effects of ACE inhibitors on mortality in people also taking aspirin (acetylsalicylic acid).ObjectiveWe performed this study to determine whether there is a reduction in the beneficial effects of ACE inhibitors on mortality in elderly people with heart failure also taking aspirin.Participants822 patients discharged from hospital wards with a diagnosis of heart failure participated in the GIFA (Italian Group of Pharmacoepidemiology in the Elderly) study.MeasurementsWe analysed the characteristics of the participants according to the type of therapy prescribed (no ACE inhibitor/no aspirin, ACE inhibitor/no aspirin, no ACE inhibitor/aspirin and ACE inhibitor/aspirin). We calculated the hazard ratios (HRs) for dying associated with each of these treatments, and calculated the synergy index to identify any negative interaction between ACE inhibitor and aspirin.ResultsThe mean age of study participants was 79 ± 7.3 (SD) years. Of the 629 (76.5%) patients discharged on ACE inhibitor and/or aspirin therapy, 31.0% were taking both drugs. Compared with no therapy with ACE inhibitor or aspirin, the HR for death was 0.65 (95% CI 0.31, 1.36) for aspirin users, 0.45 (95% CI 0.27, 0.74) for ACE inhibitor users and 0.37 (95% CI 0.19, 0.70) for ACE inhibitor/ aspirin users. The synergy index was 0.98 (95% CI 0.34, 2.80), suggesting no interaction between the drugs.ConclusionsOur data do not support the existence of a negative interaction between ACE inhibitors and aspirin in elderly patients with heart failure.

Effects of l‐ and d‐arginine and some related esters on the cytosolic mechanisms of α‐thrombin‐induced human platelet activation

1 In Fura‐2 preloaded human platelets, the increase in cytosolic calcium induced by α‐thrombin was reduced by some l‐ and d‐arginine ester compounds the IC50 (μm) values of which were 7.4 for TAEE, 56.9 for BAEE, 77.6 for TAME, 560 for T(d)AME, 656.3 for l‐ArgOMe and 2206.7 for d‐ArgOMe. α‐tosyl‐l‐Arginine, l‐ and d‐arginine were inactive. 2 The inhibitory activity of the l‐arginine esters was not modified when platelets were pretreated with 100 μm Nω‐monomethyl‐l‐arginine. 3 The l‐arginine esters did not increase cyclic GMP content in platelets either in the presence or absence of indomethacin and apyrase at rest and after α‐thrombin stimulation. 4 The kinetic parameters of platelet Na+/H+ antiporter (amiloride‐inhibitable, evaluated after cytosolic nigericin‐induced acidification) were modified by l‐ and d‐arginine esters, while the native amino acids were ineffective. 5 The inhibitory effects of the l‐ and d‐arginine esters on platelet activation appear to be mainly due to their inhibitory effect on Na+/H+ antiporter.

Intensive monitoring programme of adverse drug reactions In emergency department (MEREAFaPS Study): the Tuscan experience

Objectives: Individual case safety reports (ICSRs) could be an important source in giving further information to characterize the risk situation and aid in the prevention, diagnosis, management and treatment of adverse drug reactions (ADRs). The aim was to determine whether and where on the ICSRs clinically useful information was specified for rare ADRs in the paediatric population. Methods: ICSR concerning rhabdomyolysis occurring during use of antipsychotic medicines for patients up to 17 years of age were retrieved from the WHO Global ICSR database, VigiBase. The original case reports were requested and received from the national pharmacovigilance centres. We focused on five areas of information specified in a recent guideline for publishing ADRs.[1] Results: Eighteen original cases with an age span from 5 to 17 years were reviewed with the following outcomes. Circumstances preceding the reaction: 9 reports included this information, consisting primarily of abdominal, muscle and back pain. In eight of these reports, the full account of the symptoms and sequence of events were only found in the narratives. Underlying risk factors for rhabdomyolysis: Recorded for four of five patients in the narrative: seizures (n = 1), strenuous physical activity (n = 2), diabetic ketoacidosis (n = 1), alcohol use (n = 1). Four patients had Neuroleptic Malignant Syndrome (NMS) co-reported. Physical examination and laboratory tests: All values for patient temperature and laboratory values were given in free text. Elevated creatine phosphokinase (CPK) or myoglobin values were recorded in 14 reports ranging from 1200 to 95 000 IU/L (CPK). Patient temperature was specified for 5 patients, of whom 3 patients were also reported to experience NMS. Drug-reaction time-to-onset: 13 reports included information on the duration from drug start to reaction onset, which ranged from 4 days to 1.5 years. 9 reports included dates in the structured data, so that time to onset could be calculated and in 4 reports the information was specified in the narratives. Treatment of the reaction: Apart from stopping the drug (n = 18) and hospitalization (n = 16), other actions of treatment, such as forced intravenous fluids or resolving spontaneously, was given for 5 cases in the narrative. Conclusions: This study showed that useful clinical information was available to characterize the risk situation for these patients in this subset of reports. This should be regarded in the context that ICSRs are generally considered to be of poor quality. However, access to the free text fields recorded by the reporter was crucial to capture this information. Reference 1. Kelly WN, Arellano FM, Barnes J, et al. Guidelines for submitting adverse event reports for publication. Drug Saf 2007; 30 (5): 367-73

Iloprost antagonizes the increase in internal calcium concentration induced by α-thrombin in human platelets: A study of desensitization

SummaryWe studied the interaction between the synthetic prostacyclin analog iloprost and the aggregating agent α-thrombin by measuring the internal calcium ion concentration ([Ca2+]i) of human fura-2-loaded platelets. Iloprost (0.003–100 µg/l) did not modify the resting calcium level; when added 2 minutes before exposure of the platelets to a submaximally active concentration of α-thrombin (10 U/l), iloprost dose-dependently antagonized the increase in [Ca2+]i. To evaluate if iloprost retained this antagonistic effect even after a prolonged contact, which is well known to cause a “desensitization” phenomenon, platelets were prein-cubated with iloprost (35 µg/l) for 3 hours. After washout, the effect of newly added iloprost (0.01–100 µg/l) on the α-thrombin-induced increase in [Ca2+]i was tested. Iloprost was still able to antagonize the increase in [Ca2+]i induced by α-thrombin in “desensitized” platelets; however, the dose-inhibitory response curve was significantly shifted to the right when compared with that obtained in control platelets (i.e., platelets preincubated for 3 hours with iloprosts solvent), and the resulting IC50 was significantly higher: 1.78 versus 0.2 µg/l (p<0.001). Since the maximal inhibitory effect of iloprost could also be reached under these experimental conditions, we conclude that iloprost retains its ability to antagonize the increase in [Ca2+]i induced by α-thrombin in desensitized platelets.