Efficacy and safety of dabigatran in a "real-life" population at high thromboembolic and hemorrhagic risk: data from MonaldiCare registry.

OBJECTIVE: Dabigatran is a novel target specific oral anticoagulant for stroke prevention in non valvular atrial fibrillation. Little is still known about its real-world effectiveness and safety in the italian population. Aim of our study was to evaluate the efficacy and safety of dabigatran in a large single-center cohort of "real-life" italian population with non-valvular AF and to compare the results with those obtained from the RE-LY trial and the Medicare study. PATIENTS AND METHODS: We studied a prospective cohort of 2108 patients (1119 male; mean age 69.4 ± 9.4 years) who started the oral anticoagulant treatment with dabigatran 110 mg twice-daily (DAB 110; N = 1075; 51%) or 150 mg twice-daily (DAB 150; N = 1033; 49%). Follow-up data were obtained trough outpatients visits each 3-6 months for assessing the clinical status, adherence to treatment, occurrence of side effects and major cardiovascular complications. RESULTS: In DAB 150 group the mean age was 64.9 ± 8.8 years, 56.8% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 94.3% and HAS-BLED was ≥ 3 in 59.7%. In DAB 110 group (N = 1075) the mean age was 73.9 ± 7.5 years; 49.5% of patients was male. CHA2DS2Vasc Score was ≥ 3 in 73.4% and HAS-BLED was ≥ 3 in 87.4% of DAB 110 patients. One patient taking Dabigatran 110 mg bid had ischemic stroke without significantly neurological sequelae. In both groups, no patient experienced hemorrhagic stroke during the follow-up period. 147 patients (6.9%) of MonaldiCare population reported adverse effects from treatment with dabigatran, of whom 121 patients (5.7%) discontinued therapy. We reported one case of subarachnoid hemorrhage (0.05%) in a patient with high thrombo-embolic and high hemorrhagic risk score who was taking dabigatran 150 mg bid and one case (0.05%) of bladder bleeding in a patient who was taking dabigatran 110 mg bid. No major gastrointestinal bleeding was observed in the MonaldiCare population. CONCLUSIONS: MonaldiCare registry showed a safety profile of both dosages of dabigatran regarding major of fatal bleeding in a "real life" single center italian population at high thromboembolic and hemorrhagic risk. The majority of MonaldiCare patients tolerated dabigatran treatment without significant side effects. The efficacy of dabigatran was demonstrated by very low prevalence of ictus/TIA, also when patients underwent electrical AF cardioversion independently of the transesophageal examination.

Supercritical antisolvent precipitation of nimesulide: preliminary experiments.

The purpose of this preliminary study was to investigate the physico-chemical properties of nimesulide precipitated by continuous supercritical antisolvent (SAS) from different organic solvents like acetone, chloroform and dichloromethane at 40 degrees C and 80, 85 and 88 bar, respectively. Scanning electron microscopy, differential scanning calorimetry, X-Ray diffractometry and in vitro dissolution tests were employed to study how the technological process and the solvent nature would affect the final product. SAS-processed nimesulide particles showed dramatic morphological change in crystalline structure if compared to native nimesulide, resulting in needle and thin rods shaped crystals. The solid state analysis showed that using chloroform or dichloromethane as a solvent the drug solid state remained substantially unchanged, whilst if using acetone the applied method caused a transition from the starting form I to the meta-stable form II. So as to identify which process was responsible for this result, nimesulide was further precipitated from the same solvent by conventional evaporation method (RV-sample). On the basis of this comparison, the solvent was found to be responsible for the re-organization into the different polymorphic form and the potential of the SAS process to produce micronic needle shaped particles, with an enhanced dissolution rate if compared to the to the pure drug, was ascertained. Finally, the stability of the nimesulide form II, checked by DSC analysis, was ruled on over a period of 15 months.

A phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer.

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m(2) on days 1-3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m(2) is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.

p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma.

PURPOSE: The p53 gene plays a critical role in cellular response to DNA damage and has been implicated in the response to platinum compounds in ovarian carcinoma patients. Because taxanes could induce p53-independent apoptosis, we assessed the relevance of p53 gene status to response in ovarian carcinoma patients receiving paclitaxel and platinum-containing chemotherapy. PATIENTS AND METHODS: Forty-eight previously untreated patients with advanced disease received standard paclitaxel/platinum-based chemotherapy. In tumor specimens collected at the time of initial surgery, before therapy, p53 gene status and expression were examined by single-strand conformation polymorphism, sequence analysis, and immunohistochemical analysis. Microsatellite instability analysis was performed on available samples from 30 patients. RESULTS: Thirty-four (71%) of the 48 patients had a clinical response. Pathologic complete remission was documented in 13 (27%) of 48 patients. p53 mutations were detected in 29 (60%) of 48 tumors. Among the patients with mutant p53 tumors, 25 patients (86%) responded to chemotherapy. Only nine (47%) of 19 patients with wild-type p53 tumors responded to the same treatment. The overall response rate and the complete remission rate were significantly higher among patients with mutant p53 tumors than among patients with wild-type p53 tumors (P: =.008). Most of the tested tumors not associated with complete remission (10 of 12 tumors) were also characterized by microsatellite instability. The complete remission rate was higher among patients with tumors without microsatellite instability (five of seven patients). CONCLUSION: In contrast to the limited efficacy of treatment with paclitaxel in combination with standard platinum doses against wild-type p53 ovarian tumors, patients with mutant p53 ovarian tumors were more responsive to paclitaxel-based chemotherapy. The pattern of response to chemotherapy containing paclitaxel is different from that associated with high-dose cisplatin therapy. Determining p53 mutational status can be useful in predicting therapeutic response to drugs effective in ovarian carcinoma.

Unusual recurrence of cervical adenosquamous carcinoma after conservative surgery.

The use of less radical procedures for the treatment of early cervical cancers is gaining interest among physicians and young patients. Some authors have described surgical procedures aimed at reducing the surgical aggressiveness but the safety of such procedures remains debated. After a polypectomy, a young patient had a diagnosis of stage Ia(2) cervical adenosquamous carcinoma in 1995. As she wished to preserve her fertility, she underwent a cone biopsy and pelvic lymphadenectomy, without evidence of tumor spread. In 1998, at the 13th week of gestation, she had a diagnosis of a pelvic mass. The mass was a recurrence of carcinoma involving the myometrium, just underneath the peritoneum. She underwent a radical hysterectomy with bilateral oophorectomy. An ovarian metastasis was also detected at pathological exam. She received chemotherapy postoperatively and remains alive without evidence of disease. The recurrence of cervical cancer is traditionally regarded as an issue concerning the cervix, the parametria, or the lymph nodes. When the uterus is preserved we must also consider the possibility of a recurrence involving the corpus. With wider acceptance of limited therapeutic approaches we must be prepared for the detection of previously unknown patterns of recurrence and the follow-up modalities must be consequently adapted.

Early-stage epithelial ovarian cancer: an overview.

The clinical treatment of malignant epithelial ovarian cancer limited to the gonad(s) involves many problems that have given rise to analyses in recent literature and to different approaches: i. intensive anatomo-radio-surgical staging, evaluation and clinical incidence of prognostic risk factors; ii. re-staging of patients after inadequate and incomplete surgery; iii. indications, role and topicality of second-look surgery; iv. conservative surgery in patients of a fertile age wishing to have children and retain activity of the gonads; v. laparoscopic surgery for treatment, staging, re-staging and surveillance; vi. the lymph node issue; vii. adjuvant therapy: indications, options, type of drugs, doses and length; viii. quality and frequency of surveillance; ix. malignant epithelial ovarian cancer limited to the gonads in pregnancy. The clinical handling of these tumours entails many complex problems causing emotional involvement since it is most frequent at a fertile age.

Influence of volume expansion on hemodynamic effects of atrial natriuretic factor in rabbits.

We investigated the influence of acute volume expansion on the hemodynamic and renal responses to the constant infusion of atrial natriuretic factor (ANF) (alpha-human ANP, 2 micrograms/kg bolus, 0.2 microgram.kg-1.min-1) in rabbits anesthetized with ketamine and acepromazine. The effects of the peptide were evaluated in 12 euvolemic rabbits and in 15 rabbits during the steady-state phase of volume expansion (0.9% NaCl 4.5 ml/min for 60 min). In the euvolemic animals, ANF caused an increase in natriuresis and a reduction in blood pressure (BP), which was associated with a decrease in cardiac output (CO), stroke volume (SV), and no significant changes in central venous pressure (CVP), peripheral hematocrit (Hct), and heart rate (HR). When the peptide was infused in the volume-expanded animals, the effects of ANF on BP and HR were comparable with those observed in the euvolemic animals. However, in these animals the ANF-induced changes in CO, SV, CVP, and Hct were significantly greater than those observed in the euvolemic group. In addition, the percent increases in diuresis and natriuresis were significantly smaller than those obtained in the euvolemic animals. In conclusion, volume expansion with saline potentiates the effects of ANF on systemic hemodynamics and blood volume.

Hemodynamic responses to atrial natriuretic factor in nephrectomized rabbits: attenuation of the circulatory consequences of acute volume expansion.

We investigated the hemodynamic responses to three doses of atrial natriuretic factor [human atrial natriuretic factor-(99-126)] (ANF) in nephrectomized rabbits anesthetized with ketamine and acepromazine. The influence of the different doses of the peptide on the hemodynamic consequences produced by acute volume expansion (0.9% NaCl, 1.4 ml/kg/min for 60 minutes) was also studied. All three dosages of ANF (0.001, 0.01, and 0.2 micrograms/kg/min for 20 minutes) significantly reduced blood pressure. With the lowest dose, the hypotensive effect was associated with reduction in systemic vascular resistance and no significant change in heart rate, stroke volume, central venous pressure, and hematocrit. In contrast, the intermediate and high doses, which resulted in markedly higher plasma levels, caused a significant decrease in heart rate, central venous pressure, and stroke volume; a slight rise in hematocrit; and no change in systemic vascular resistance. Volume expansion produced by saline infusion in an additional group of nephrectomized rabbits increased central venous pressure and decreased hematocrit. When ANF infusion was associated to volume expansion, each dosage of ANF was able to reduce the rise in central venous pressure, while only the higher dosage attenuated the progressive fall in hematocrit caused by volume expansion. Plasma volume, measured at the end of volume expansion was lower in the group treated with the highest dose of ANF than in the control animals (28.2 +/- 9 vs. 35.1 +/- 3 ml/kg, p less than 0.05). We conclude that 1) ANF induces significant hemodynamic effects independently from its renal action.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor potentiates forearm reflex vasoconstriction induced by cardiopulmonary receptor deactivation in man.

Previous evidence suggests that atrial natriuretic factor (ANF) interferes with the autonomic control of circulation. In the present study we investigated whether ANF modulates forearm vasoconstriction reflexly induced by cardiopulmonary receptor unloading in man. For this purpose, the hemodynamic response to -20 mm Hg lower body negative pressure (LBNP) was assessed under control conditions and during the constant infusion of alpha-human ANF (0.5 micrograms/kg bolus followed by 0.05 micrograms/kg/min) in seven normal subjects. ANF infusion resulted in a slight reduction in blood pressure and right atrial pressure, did not modify heart rate or forearm vascular resistance, but significantly potentiated the reflex increase in forearm vascular resistance during LBNP (+25 +/- 9% under control conditions vs +40 +/- 12% during ANF, p less than .05). In an attempt to clarify the mechanisms underlying the enhanced reflex vasoconstriction during infusion of ANF, in five additional subjects we demonstrated that there was a comparable vascular reflex response to LBNP under control conditions and during nitroglycerin infusion at a dose that induced a reduction in atrial pressure comparable to that observed during ANF. Finally, in seven additional subjects we found that ANF infusion did not alter the reflex hemodynamic responses elicited by carotid baroreceptor unloading induced by a +60 mm Hg increase in external neck pressure. We conclude that during the infusion of a pharmacologic dose of ANF the reflex forearm vasoconstriction in response to selective cardiopulmonary receptor unloading is potentiated. This effect does not seem to be related to the hemodynamic actions of the peptide or to interference with the sympathetic control of peripheral circulation.

Efficacy of once-daily urapidil treatment in mild or moderate essential hypertension assessed by ambulatory 24-hour blood pressure monitoring.

The blood pressure-lowering effect and tolerability of urapidil 120 mg once daily versus urapidil 60 mg twice daily was compared in 36 outpatients with newly diagnosed mild to moderate essential hypertension. Patients were enrolled in the study if they showed a favourable response to urapidil 60 mg twice daily at the end of a 2-week run-in as revealed by a first non-invasive 24-hour blood pressure profile. The patients were then randomly allocated to a 6-week double-blind treatment with either urapidil 120 mg once daily or urapidil 60 mg twice daily. Blood pressure, heart rate and adverse reactions were recorded every 2 weeks in the morning before drug intake. A second 24-hour blood pressure profile was taken at the end of this treatment phase. Compared with the pretreatment value after placebo run-in, urapidil 60 mg twice daily lowered supine morning blood pressure from 159/103 to 138/89. Urapidil 120 mg once daily lowered blood pressure from 161/102 to 139/90. The decrease in blood pressure was statistically significant within (p less than 0.001) but not between the treatment groups. Similar results were obtained with standing blood pressures. Side effects were observed in 2 patients with urapidil 60 mg twice daily (dizziness, intermittent lack of ejaculation) and in 7 patients with urapidil 120 mg once daily (5 with dizziness, and 1 each with headache and palpitations). Thus, urapidil 120 mg once daily lowers elevated blood pressure throughout a 24-hour period as effectively as 60 mg twice daily. Therefore, during long term therapy, the tolerability but not the efficacy of urapidil appears to be directly related to its peak serum concentrations.

Influence of atrial natriuretic factor on forearm reflex vasoconstriction induced by cardiopulmonary or arterial receptor unloading.

We studied the influence of atrial natriuretic factor (ANF) infusion on the reflex increase in forearm vascular resistance in normotensive subjects. Reflex vasoconstriction was induced by cardiopulmonary receptor unloading [lower body negative pressure (LBNP), -20 mmHg for 15 min] or by carotid baroreceptor deactivation (+60 mmHg increase in external neck pressure by a pneumatic neck-chamber). Atrial natriuretic factor induced a significant increase in the reflex forearm vasoconstriction to LBNP, but did not modify systemic and regional reflex haemodynamic responses to carotid baroreceptor deactivation. These results suggest that ANF has important interactions with the neural control of peripheral circulation. In addition, the study shows that the peptide causes a selective potentiation of the reflex vasoconstrictor response evoked by cardiopulmonary receptor unloading.

Vagal mediation of the effects of atrial natriuretic factor on blood pressure and arterial baroreflexes in the rabbit.

We investigated the hemodynamic effect of synthetic atrial natriuretic factor Auriculin A (ANF) and its influence on arterial baroreflex control of heart rate, systemic blood pressure, and perfusion pressure in the hind limb (perfused at constant flow) in rabbits anesthetized with alpha-chloralose and urethane. The neural mechanisms underlying these effects were also studied. In the intact animal, a 45-minute constant infusion of ANF (2 micrograms/kg prime, 0.2 microgram/kg/min) significantly reduced mean blood pressure and increased mean perfusion pressure, while heart rate did not change. Comparable data were obtained with lower (0.5 microgram/kg + 0.05 microgram/kg/min; 1 microgram/kg + 0.1 microgram/kg/min) or higher (4 micrograms/kg + 0.4 microgram/kg/min; 8 micrograms/kg + 0.8 microgram/kg/min) doses of ANF. In addition, ANF enhanced bradycardic reflex responses to phenylephrine i.v. bolus administration, while it did not change baroreflex-mediated responses to nitroglycerin i.v. bolus administration and to 30-second bilateral carotid occlusion. The specificity of the influence of ANF on arterial baroreflex responses was confirmed by the observation that no significant change in reflex responses to phenylephrine or carotid occlusion was detectable during a comparable decrease in blood pressure induced by a constant infusion of nitroglycerin. Bilateral vagotomy prevented both the fall in blood pressure and the increase in perfusion pressure induced by ANF, while cholinergic blockade (atropine, 0.5 mg/kg i.v.) or adrenergic blockade (propranolol, 0.3 mg/kg i.v. + phentolamine, 0.3 mg/kg i.v.) did not modify the hemodynamic response to ANF observed in the intact animal.(ABSTRACT TRUNCATED AT 250 WORDS)