Enrico Boschetti

Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone : a randomized single-blind study

To prevent delayed emesis induced by cisplatin (mean dose 90 mg/m2), 120 consecutive patients were randomized to receive, in a 7-day crossover design, oral metoclopramide (20 mg q.i.d.), dexamethasone (1 mg q.i.d.) or placebo (two tablets q.i.d.) starting 24 hours after the end of chemotherapy. Complete protection from nausea, but not from vomiting. was significantly increased by both dexamethasone and metoclopramide with respect to placebo. Important prognostic factors favoring the appearance of delayed emesis were incomplete protection from vomiting during the first 24 hours after cisplatin, female gender, and highest cisplatin doses. Tolerability of both drugs was good. Larger and randomized controlled trials are necessary to identify better preventive treatment of delayed emesis induced by cisplatin.

Contribution of Autonomic Neuropathy to Reduced Plasma Adrenaline Responses to Hypoglycemia in IDDM: Evidence for a Nonselective Defect

To determine the contribution of clinically overt diabetic autonomic neuropathy (DAN) to reduced plasma adrenaline responses to hypoglycemia in IDDM and to establish its selectivity for hypoglycemia, we studied 17 IDDM patients (7 without DAN [DAN−] and 10 with DAN [DAN+]), of whom 5 had and 5 did not have postural hypotension (DAN+PH+ and DAN+PH−, respectively), and 8 nondiabetic subjects on 2 different occasions, i.e., clamped hypoglycemia (steps from 5.0 to 2.2 mmol/l plasma glucose) and 30-min steady-state exercise at 55% VO2max. Recent antecedent hypoglycemia was meticulously prevented before the studies to exclude hypoglycemia as a cause of reduced responses of adrenaline to hypoglycemia. In DAN− patients, maximal responses of adrenaline to hypoglycemia were reduced (2.44 ± 0.58 nmol/l vs. 4.9 ± 0.54 nmol/l in nondiabetic patients) (P < 0.05). In DAN+, adrenaline responses initiated at a lower plasma glucose and were lower than in DAN− (DAN+PH−, 1.06 ± 0.38 nmol/l; DAN+PH+, 0.84 ± 0.27 nmol/l; P < 0.001, but NS between PH− and PH+). In response to exercise, adrenaline increased less in DAN− (0.89 ±0.11 nmol/l) patients than in nondiabetic subjects (1.19 ± 0.14 nmol/l; NS) and only to 0.36 ± 0.07 nmol/l in DAN+PH− and 0.23 ± 0.09 nmol/l in DAN+PH+ (P < 0.001 vs. DAN− and nondiabetic subjects). These results were confirmed when nondiabetic and DAN− subjects repeated the exercise at 60 watts (35 and 41% of Vo2max, respectively), i.e., at the same absolute workload of DAN+ patients. Thus, DAN (both PH+ and PH−) contributes to reduced responses of adrenaline to hypoglycemia independently of recent antecedent hypoglycemia. The adrenaline defect in DAN is not selective for hypoglycemia.

Pharmacokinetics of vincristine in cancer patients treated with nifedipine

The pharmacokinetics of vincristine (VCR) after an intravenous bolus dose of 2 mg were studied in patients with cancer with and without a concomitant treatment with the calcium‐entry blocker nifedipine (NIF). VCR concentrations were determined by a sensitive radioimmunoassay. Pharmacokinetic data were analyzed by a nonlinear weighted least‐square regression program (SAS‐NLIN). A tri‐exponential model fitted the raw data better than a bi‐exponential model in five of 14 (35%) patients treated with VCR alone and in seven of 12 (58%) patients treated with VCR plus NIF (P = NS). The T1/2α was shorter in NIF‐treated patients, whereas the T 1/2γ was longer in the NIF‐treated group. The NIF‐treated group showed an increase in the AUC O‐∞ and AUC 1 to 96 hours, and a decrease in the AUC 0 to 1 hour. Total plasma clearance of VCR and 7‐day urinary excretion of VCR was reduced in the NIF‐treated patients. These data suggest that, when VCR is administered to NIF‐treated patients with cancer, there is a decrease in VCR clearance from the body. Theoretically, a greater cytotoxicity may be anticipated.

Platelets release active matrix metalloproteinase-2 in vivo in humans at a site of vascular injury: lack of inhibition by aspirin

When stimulated in vitro, human platelets release matrix metalloproteinase‐2 (MMP‐2) that, in turn, potentiates platelet activation. The present study investigated if MMP‐2 is released from activated platelets in vivo in humans and whether aspirin inhibits this release. MMP‐2 levels were measured by zymography, immunoblotting, flow‐cytometry and an activity assay system, in plasma prepared from blood emerging from a skin wound inflicted for the measurement of the bleeding time (shed blood) and simultaneously from venous blood in 27 healthy human volunteers. In a subgroup, the same measurements were carried out before and 1 h after aspirin intake. MMP‐2 was significantly higher in shed blood than in venous blood and increased progressively, consistent with ongoing platelet activation. A significant correlation was evident between platelet number and MMP‐2 in shed blood; platelet MMP‐2 content in shed blood was lower than that of platelets in venous blood. The level of active MMP‐2 released by activated platelets in vivo was within the range of concentrations that potentiate platelet activation. Aspirin did not reduce MMP‐2 release in vivo. In conclusion, MMP‐2 is released from platelets in vivo in humans at a localised site of vessel wall damage in amounts sufficient to potentiate platelet aggregation; aspirin does not reduce this release.

Prolonged Antithrombin Activity of Low-Molecular-Weight Heparins Clinical Implications for the Treatment of Thromboembolic Diseases

BACKGROUND The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay. METHODS AND RESULTS We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10,000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours. CONCLUSIONS Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.

Interferon-Alpha Is Effective in the Treatment of HIV-1–Related, Severe, Zidovudine-Resistant Thrombocytopenia: A Prospective, Placebo-controlled, Double-Blind Trial

Thrombocytopenia is relatively common in patients infected with human immunodeficiency virus type 1 (HIV-1), and it occurs in patients belonging to all major risk groups, such as homosexuals, intravenous drug users, and hemophiliacs [1-3]. Thrombocytopenia occurs in 5% to 15% of asymptomatic patients; 6% to 24% of these patients have serious thrombocytopenia (counts < 30 109/L [2, 4]) and clinical bleeding [2, 4, 5]. The general consensus is to not treat patients with less severe thrombocytopenia because of the low risk for bleeding and the possibility of spontaneous remissions [6-9]. However, the treatment of severe thrombocytopenia is mandatory in view of the frequent, serious bleeding manifestations [2, 4, 5]. The mechanism of HIV-1related thrombocytopenia is not completely understood but immunologic mechanisms (antiplatelet antibodies or circulating immune complexes, or both) and megakaryocyte viral infection may play a role [10]. Although the response to treatment of HIV-1related thrombocytopenia does not appear to differ substantially from that observed in adults with idiopathic chronic thrombocytopenia, there are limitations when using conventional therapeutic approaches. Steroids and other immunosuppressive agents (for example, vincristine, cyclophosphamide) [11, 12] can facilitate the development of opportunistic infections or can lead to the flaring up of infectious hepatitis, which is often present in these patients [13, 14]; steroids have also been reported to accelerate the progression of Kaposi sarcoma [15, 16]. Splenectomy enhances the risk for subsequent infection, especially severe sepsis [17], and in some patients a late relapse of thrombocytopenia may occur [18]. High-dose intravenous immunoglobulins represent an effective treatment in most patients, but the effect is short-lasting in almost all of them, and the high costs and the need for intravenous administration limit their use [9, 19]. Finally, alternative approaches, such as dapsone [20], protein A immunoadsorption [21], or anti-rhesus factor IgG [19], have been tested in limited series and uncontrolled studies (or both). It is now well established that zidovudine (azidothymidine) can effectively enhance the platelet count of patients with HIV-1related thrombocytopenia. A remission of thrombocytopenia during zidovudine administration has been shown in several case series [22-24] and in one placebo-controlled, prospective clinical study [25]. However, between 30% and 40% of patients with thrombocytopenia are resistant to full-dose (1000 mg/d) zidovudine treatment [23, 24, 26, 27]. It is not clear that higher doses of zidovudine affect thrombocytopenia [28, 29]; in addition, higher doses are potentially toxic [30]. Some anecdotal reports and small, uncontrolled case series have recently suggested that interferon- can correct the thrombocytopenia of patients with HIV-1 infection [9, 14, 31-33], even in patients not responding to zidovudine treatment [31, 33]. However, no studies have analyzed, under carefully controlled conditions, the efficacy, toxicity, and kinetics of the response to interferon- in patients with zidovudine-resistant, HIV-1related thrombocytopenia. We tested whether interferon- can increase the platelet count in patients with zidovudine-resistant, HIV-1related severe thrombocytopenia and assessed the kinetics of the interferon- effects and the possible toxicity of interferon in association with zidovudine in a randomized, placebo-controlled clinical study. Methods Selection of Patients Patients were considered eligible for the study if they were seropositive for HIV-1 by the enzyme-linked immunosorbent assay and the Western-blot technique and had a platelet count less than 25 109/L on at least two occasions separated by more than 2 weeks. In addition, thrombocytopenia had to be refractory to a 1-month course of full-dose (1000 mg/d) zidovudine treatment and to previous therapeutic attempts with one of the following: corticosteroids, splenectomy, vincristine, danazol, high-dose intravenous IgG, or anti-ID immunoglobulins. The main exclusion criteria were pregnancy or breast-feeding; the acquired immunodeficiency syndrome; concomitant serious diseases not related to HIV-1 infection (cardiomyopathy, seizure, stroke, psychosis); presence of antinuclear, anti-smooth-muscle, antimitochondrial, or anti-liver-kidney microsome 1 antibodies; and granulocyte counts less than 1 109/L or hemoglobin levels less than 80 g/L. Women of childbearing potential were advised to practice effective methods of birth control. Assessment before study included a medical history, physical examination, electrocardiogram, chest radiograph, and the following laboratory tests: measurement of hemoglobin, hematocrit, mean corpuscular volume, leukocyte count, differential leukocyte count, platelet count, serum glucose, blood urea nitrogen, serum creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serologic tests for hepatitis B and C, prothrombin time, activated partial thromboplastin time, bleeding time, and urinalysis. Fifteen consecutive patients satisfying the criteria for entry into the study were enrolled between April and October 1992 in four centers belonging to four different hospitals in Central Northern Italy. Written, informed consent was obtained from each patient before enrollment in the study; the study protocol was approved by the Ethics Committee of the Umbria Region. Treatment Patients were enrolled in a double-blind, crossover, placebo-controlled, randomized study in which they were treated with either subcutaneous lymphoblastoid interferon- (Wellferon, Burroughs Wellcome, Italy) or 1 mL of subcutaneous saline solution (placebo). Therapy was administered to the patients in hospital by specially trained nurses. The treatment code was known only to the nurse, and the doctors, nurses involved in patient management, and the patients were all blinded to the study code. All patients received subcutaneous injections of placebo or interferon-, 3 million units, three times a week for 4 weeks. During the following 4 weeks, they did not receive any injections (washout period); they were then switched to the opposite treatment for another 4 weeks. After treatment discontinuation, patients were followed for a final 4-week period (washout period). Patients were randomly assigned to either sequence of the crossover design. The study lasted 16 weeks; during this time patients were seen weekly for clinical evaluations including a physical examination, a review of subjective complaints, and standard hematologic tests including platelet counts. All patients received, throughout the study period, zidovudine therapy at 200 mg three times a day. Bleeding times, immune studies, and p24 antigen, hematologic, renal, and hepatic tests were done at weeks 0, 4, 8, 12, and 16. Evaluation Criteria The primary end point, established before the beginning of the study, was the variation in the number of circulating platelets. A secondary end point was the clinical response to interferon- treatment, defined as follows: 1) complete response: platelet count more than 100 109/L; 2) partial response: platelet count more than 50 109/L and less than 100 109/L; 3) failure: platelet count less than 50 109/L. A cut-off level of 50 109 platelets/L was chosen to define treatment failure because conventionally hemorrhage is rare when counts are greater than this limit. Other secondary end points included the bleeding time, p24 antigen levels in serum, CD4 and CD8 counts, 2-microglobulin levels in serum, and platelet-associated IgG. Laboratory Data Platelet counts were determined on ethylenediaminetetraacetic acid-anticoagulated venous blood samples by using electronic particle counters (Coulter Counter, STKR, Hialeah, Florida for the four centers). Platelet counts were measured on each patient using the same instrument throughout the study. Bleeding time was carried out according to Mielke and colleagues [34] by the use of a standardized template (Simplate II, General Diagnostics, Morris Plains, New Jersey). The registration of the bleeding time was followed for a maximum of 30 minutes; when the bleeding time exceeded 30 minutes, it was considered to be equal to 30 minutes for the statistical analysis. CD4 and CD8 lymphocyte counts were determined by two-color flow cytometry using monoclonal antibodies (Leu 2-3+, Leu 2+3-; Leu 4+Dr-; Becton Dickinson, Franklin, New Jersey) on whole blood samples. Serum p24 core antigen was determined by enzyme immune assay (New England Nuclear, du Pont, Rockville, Maryland); the least detectable amount with this assay is 4.4 pg/mL of serum. Serum 2-microglobulin was assayed by enzyme immune assay (Behring, Scoppito, Italy). Serum platelet antibodies were detected with the indirect platelet suspension immunofluorescence test [35]. Determinations of hemoglobin, complete blood counts, serum glucose, blood urea nitrogen, creatinine, liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, -glutamyltranspeptidase, and total bilirubin), prothrombin time, and activated partial thromboplastin times were carried out according to standard procedures. Data Collection and Statistical Analysis All investigators, nurses, and laboratory personnel involved in patient and sample management were blinded to treatment groups until all end points were determined at the end of the study. First-order carryover identifies the residual effect of a given treatment at the time of the second baseline (before the beginning of the second treatment), whereas second-order carry-over indicates any residual effect of the first treatment at the time of the second treatment. Data required by the study protocol were collected and recorded in case report forms by the investigators at each of the participating centers. The case report forms were then submitted to clinical research personnel at the

Importance and limits of pre-hospital electrocardiogram in patients with ST elevation myocardial infarction undergoing percutaneous coronary angioplasty

Background: The purpose of this study is to present data on the effects of pre-hospital electrocardiogram (PH-ECG) on the outcome of ST elevation myocardial infarction (STEMI) patients treated with percutaneous coronary angioplasty (PCI) included in a registry undertaken in the Italian region of Lombardy. Pre-hospital 12-lead electrocardiogram is recommended by current guidelines in order to achieve faster times to reperfusion in patients with STEMI. Methods: The registry includes 3901 STEMI patients who underwent primary PCI over an 18-month period. Results: Mean age was 63 ± 12 years. Admission through the emergency medical system (EMS) occurred in 1603 patients (40%): they were older, more frequently had previous MI, TIMI flow = 0 at entry and were more frequently in Killip class >1 than patients who were not admitted through the EMS. Among the patients admitted through the EMS, PH-ECG was obtained in 475 patients (12%). These patients had less frequently an anterior MI, but more frequently had absence of TIMI flow at entry than patients whose ECG was not teletransmitted. Moreover, they had a significantly shorter first medical contact-to-balloon time and a trend toward a lower 30-day death rate (5.3% vs 7.9 %, p = 0.06). However, only patients in Killip class 2–3 had a significantly lower mortality when the diagnostic ECG was transmitted, whereas no difference was found in Killip class 1 or Killip class 4 patients. Conclusions: In this registry, PH-ECG significantly decreased first medical contact-to-balloon time. Attempts to achieve faster reperfusion times should be undertaken, as this may result in improved outcome, particularly in patients with mild to moderate symptoms of heart failure.

Operator exposure to x-ray in left and right radial access during percutaneous coronary procedures: OPERA randomised study

Objective Left radial access (LRA) and right radial access (RRA) have been shown to be safe and effective for coronary arteries catheterisation. However, the differences between the two approaches in terms of radiation exposure are still unclear. The aim of the present investigation is to evaluate in a randomised study, the dose of radiation absorbed by operators using either LRA or RRA. Design Randomised, prospective, double arm, single centre study. Setting University Hospital. Patients Male or female subjects with stable, unstable angina and silent ischaemia. Interventions The present study is a comparison of LRA and RRA for coronary artery catheterisation in terms of operators’ radiation exposure. Main outcome measures The primary outcome measure was the radiation dose absorbed by operators; secondary outcome measures were fluoroscopy time, dose-area product and contrast delivered. Results A total of 413 patients were enrolled; 209 were randomly selected to undergo diagnostic procedures with RRA and 204 with LRA. The operators radiation exposure was significantly lower in the left radial group (LRA 33±37 μSv vs RRA 44±32 μSv, p=0.04). No significant differences were observed in fluoroscopy time (LRA 349±231s vs RRA 370±246 s p=0.09) and dose-area product (LRA 7011.42±3617.30 μGym2 vs RRA 7382.38±5226.61 μGym2, p=0.80), even though in both there was a trend towards a lower level in the LRA. No differences were observed in contrast medium delivered (LRA 89.92±32.55 ml vs RRA 88.88±35.35 ml, p=0.45). Conclusions The LRA was associated in the present report with a lower radiation dose absorbed by the operator during coronary angiography.

Double-blind crossover trial of single vs. divided dose of metoclopramide in a combined regimen for treatment of cisplatin-induced emesis

In a double-blind crossover antiemetic study in cisplatin-treated cancer patients, metoclopramide 4 mg/kg as a single intravenous dose (regimen A) was compared with 3 mg/kg in two doses (regimen B). In both regimens, metoclopramide was combined with dexamethasone and diphenhydramine. 65 consecutive, chemotherapy-naïve inpatients (45 males and 20 females) treated with high doses (at least 50 mg/m2) of cisplatin entered the study and 54 completed both treatments. Complete protection from vomiting and nausea, mean number of emetic episodes, mean maximum intensity of nausea and mean duration of emesis or nausea were similar with the two antiemetic regimens. 23 patients (43%) did not express a treatment preference, while 16 (30%) preferred regimen B and 15 (28%) preferred regimen A. Side-effects were similar with the two metoclopramide schedules. A combined antiemetic regimen of a single high dose of metoclopramide (4 mg/kg) can preserve efficacy and tolerability and thus should be preferred.

Effectiveness of Adjunctive Stent Implantation Following Directional Coronary Atherectomy for Treatment of Left Anterior Descending Ostial Stenosis

The aim of this study was to evaluate the acute and long-term angiographic and clinical results of optimal plaque debulking by means of directional coronary atherectomy (DCA) followed by stent implantation for treatment of left anterior descending (LAD) ostial stenosis. Eighty consecutive patients (66 men; aged 57 +/- 10 years) with angina pectoris, documented anterior myocardial ischemia, and de novo LAD ostial stenosis prospectively underwent DCA and stent deployment. They were evaluated angiographically after 6 months and clinically for up to 30 +/- 29 months. The primary success rate was 98%. The in-hospital complications were 1 death due to in-stent subacute thrombosis 7 days after the procedure, 1 non-Q-wave myocardial infarction, and 1 retrograde left main artery dissection. The angiographic binary restenosis rate was 14.5%, and the loss index was 0.38 +/- 0.35. The target lesion revascularization (TLR) rates at 6, 12, and 24 months were 6.0%, 14.5%, and 16.3%, respectively, and the combined event rates (death, nonfatal myocardial infarction, TLR) at the same times were 8.7%, 17.5%, and 21.2%, respectively. These results indicate that the combined approach of DCA and stent implantation is feasible and safe in patients with LAD ostial lesions, has a high success rate, a low incidence of restenosis, and a good long-term outcome.