Epidemiology of nosocomial infection in 125 Italian intensive care units.

AIM: A continuous infection surveillance program was conducted by GiViTI throughout 2006 in Intensive Care Units (ICUs). METHODS: This was a prospective epidemiological study carried out in 125 Italian intensive care units. All patients have been included in the study. Aside from the detailed clinical information collected for all patients, in cases of infection upon ICU admission and for the first site-specific episode that occurred during the patient's stay, the following data were collected: severity upon admission, micro-organisms and their antibiotic resistance patterns, subsequent multiple episodes in the same site, origin of infections and maximum severity reached. The diagnostic criteria for all infections are explicitly stated. RESULTS: A total of 34,472 patients entered the study. Infection upon admission was present in 12.6% of patients, with a high level of ICU and hospital mortality (29.4% and 38.7%, respectively). In 3148 patients one or more infections were reported as ICU-acquired with an overall incidence of 9.1% and an ICU and hospital mortality of 27.2% and 35.1%, respectively. Out of the device-related infections, ventilator-associated pneumonia was the most frequently diagnosed (8.9/1000 days on ventilator). Catheter-related blood stream infection was reported with a low incidence (1.9/1000 central venous catheter days). Nearly 20% of more than 5000 isolated microorganisms were classified as multi-drug resistant, with methicillin-resistant Staphylococcus aureus as the most frequently reported bug. CONCLUSIONS: The ad hoc expanded GiViTI software "Margherita2" allows continuous infection surveillance in Italian ICUs, annually providing an extensive and updated database. Interventions to improve infection prevention and patient safety should be tailored to accommodate these data.

Zygomycosis in Italy: a survey of FIMUA-ECMM (Federazione Italiana di Micopatologia Umana ed Animale and European Confederation of Medical Mycology).

The aims of the study were to analyze the clinical and epidemiological characteristics and treatments for patients who developed zygomycosis enrolled in Italy during the European Confederation of Medical Mycology of medical mycology survey. This prospective multicenter study was performed between 2004 and 2007 at 49 italian Departments. 60 cases of zygomycosis were enrolled: the median age was 59.5 years (range 1-87), with a prevalence of males (70%). The majority of cases were immunocompromised patients (42 cases, 70%), mainly hematological malignancies (37). Among non-immunocompromised (18 cases, 30%), the main category was represented by patients with penetrating trauma (7/18, 39%). The most common sites of infection were sinus (35%) with/without CNS involvement, lung alone (25%), skin (20%), but in 11 cases (18%) dissemination was observed. According to EORTC criteria, the diagnosis of zygomycosis was proven in 46 patients (77%) and in most of them it was made in vivo (40/46 patients, 87%); in the remaining 14 cases (23%) the diagnosis was probable. 51 patients received antifungal therapy and in 30 of them surgical debridement was also performed. The most commonly used antifungal drug was liposomal amphotericin B (L-AmB), administered in 44 patients: 36 of these patients (82%) responded to therapy. Altogether an attributable mortality rate of 32% (19/60) was registered, which was reduced to 18% in patients treated with L-AmB (8/44). Zygomycosis is a rare and aggressive filamentous fungal infection, still associated with a high mortality rate. This study indicates an inversion of this trend, with a better prognosis and significantly lower mortality than that reported in the literature. It is possible that new extensive, aggressive diagnostic and therapeutic procedures, such as the use of L-AmB and surgery, have improved the prognosis of these patients.

[Infection surveillance in intensive care units. Preliminary results of a multicenter GiViTI study in 71 Italian ICUs]. / La sorveglianza delle infezioni in terapia intensiva. Risultati preliminari di uno studio multicentrico GiViTI su 71 TI.

AIM: Infection surveillance and control in ICU is believed to be a means to improve the quality of assistance. The importance of this activity is supported by both epidemiological (rate and severity of infection in ICU) and economic (efficiency, cost-benefit and cost-effectiveness analysis) evaluations. Many authors thinks that infection surveillance and control should be performed with a routine tool in order to obtain remarkable data without too much time loss, and used by many ICUs, in order to compare the data. METHODS: A prospective observational study in 71 Italian ICUs participating in GiViTi. All patients admitted in each ICU during 6 month (except those discharged alive within 48 hours from admission) were enrolled and surveyed. Demographic and clinical data, data relating to nosocomial and at admission infections, risk factors, responsible micro-organisms, antibiotics use and outcome were collected. RESULTS: A total of 5814 patients (98% of eligible patients) were surveyed. The overall incidence of infected patients was 43%. The incidence of patients with nosocomial infection was 18% (1062 patients). Pneumonia, bacteraemia and urinary tract were the main sites. The major isolated micro-organism responsible of infection were staphylococcus (29.7%) and pseudomonas (16.2). Only 17% of all patients was not treated with antibiotics, and 72% of patients without infection was treated with antibiotics. CONCLUSION: These preliminary data confirm the importance of infection in ICU and the need of continuous surveillance. We propose a tool that can be useful for continuous and multicentric infection surveillance in ICU.

[Protein C and coagulation in sepsis]. / La proteina C e la coagulazione nella sepsi.

The last few years have clarified the tight link between inflammation and coagulation. In addition to the identification of new regulatory mechanisms of the coagulation system and of an explosive number of mediators of inflammation, it is now clear that the existence of a positive feed-back between inflammation and coagulation leads to reciprocal activation of both pathways. Plasma levels of acute phase proteins involved in coagulation and fibrinolysis are elevated during inflammation, while natural anticoagulant mechanisms are depressed. Pro-inflammatory cytokines "activate" cell membranes exposed to flowing blood (endothelium, platelets, monocytes, neutrophils) which from physiologically inert or anticoagulant become procoagulant. Increased tissue factor expression results in increased thrombin formation within the microcirculation. Thrombin is central to fibrin deposition but it also plays a key role in cell-mediated mechanisms involving inflammation, cell proliferation and activation of the natural anticoagulant protein C. Depression of natural anticoagulant mechanisms, occurring in severe sepsis, results in uncontrolled thrombin formation, with pro-inflammatory activity prevailing, and the feed-back loop of inflammation and coagulation ultimately leading to multi-organ failure. However, both in the clinical setting and in animal experiments, heparin or direct anticoagulants have shown no effect on survival even if blocking fibrin deposition. Organ failure is only partially due to the thrombotic occlusion of the microcirculation, while other mechanisms of endothelial damage are probably more relevant in the development of ischemia. The endothelium is central to the maintenance of the natural anticoagulant mechanisms (TFPI, antithrombin, protein C). The protein C system, in addition to dumping thrombin formation, specifically modulates inflammation by cell signaling. This system is markedly depressed in severe sepsis. The infusion of activated protein C, or restoring normal levels of protein C within the circulation - depending on the individual bleeding risk are powerful tools to treat the endothelitis responsible for the clinical sequelae of severe sepsis.

Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation.

BACKGROUND: This study retrospectively assessed, with an intention-to-treat analysis, the effect of kidney-pancreas transplantation (KP) on survival and cardiovascular outcome in type 1 diabetic uremic patients. METHODS: A total of 351 uremic type 1 diabetic patients were enrolled on a waiting list for KP: 130 underwent KP transplantation, 25 underwent kidney transplantation alone (KA), whereas 196 patients remained on dialysis (WL). The three populations had similar cardiovascular conditions. Actuarial survival rates and causes of death were recorded over a period of seven years. Finally, 23 KP and 13 KA patients underwent left radionuclide ventriculography, during a follow-up of four years. RESULTS: In the entire group of 351 patients the seven-year survival rate was 77.4% for KP, 56.0% for KA and 39.6% for WL (KP vs. WL, P = 0.01). Cardiovascular death rate was 7.6% in KP, 20.0% in KA and 16.1% in WL (KP versus WL, P = 0.03; KP vs. KA, P = 0.16). In the subsample studied with radionuclide ventriculography, left ventricular ejection fraction improved in KP, but did not in KA, with significant differences between groups at two and four years. At four years only the KP patients presented normal values of diastolic parameters, including the peak filling rate, time-to-peak filling rate, and peak filling rate/peak ejection rate ratio. Glycated hemoglobin was negatively associated with the ejection fraction, peak filling rate and peak filling rate/peak ejection rate ratio, and positively associated with the time-to-peak filling rate. CONCLUSIONS: Normalization of blood glucose metabolism and improvement of blood pressure control obtained with KP transplant is associated with positive effects on survival, cardiovascular death rate, and left ventricular function.

Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients.

OBJECTIVE: Diastolic function is frequently impaired in diabetic patients. Our aim was to evaluate the effects of glycometabolic control achieved by pancreas transplantation on left ventricular function in uremic type 1 diabetic patients. RESEARCH DESIGN AND METHODS: Left ventricular systolic and diastolic functions were evaluated using radionuclide ventriculography in 42 kidney-pancreas transplant patients and 26 kidney-alone recipients who had similar clinical characteristics before transplantation. Patients were grouped according to 6, 24, and 48 months of follow-up. Control subjects consisted of 20 type 1 diabetic patients. RESULTS: The left ventricular ejection fraction was normal in all of the patients. However, kidney-pancreas transplant patients with 4 years of graft function had a higher ejection fraction (75.7 +/- 1.8%) than kidney-alone patients with 4 years of graft function (65.3 +/- 2.8%, P = 0.02) and type 1 diabetic patients (61.3 +/- 3.7%, P = 0.004). In patients with 4 years of graft function, normal diastolic parameters were evident in kidney-pancreas but not in kidney-alone or in type 1 diabetic patients (peak filling rate: 4.46 +/- 0.15 end diastolic volume (EDV)/s in kidney-pancreas patients vs. 2.73 +/- 0.24 EDV/s [P < 0.01] and 3.39 +/- 0.30 EDV/s [P < 0.01] in kidney-alone and type 1 diabetic patients, respectively; time-to-peak filling rate: 141.9 +/- 7.8 ms in kidney-alone patients vs. 209.4 +/- 13.5 ms in kidney-alone patients [P < 0.01]; peak filling rate/peak ejection rate ratio: 1.10 +/- 0.04 in kidney-pancreas patients vs. 0.81 +/- 0.08 in kidney-alone patients [P < 0.01]). A significant reduction in diastolic dysfunction rate was observed only in kidney-pancreas patients. CONCLUSIONS: Kidney-pancreas transplantation results in complete insulin independence, a better glycometabolic pattern and blood pressure control, an improvement of left ventricular function, and a reversal of diastolic dysfunction.

[Retinoic acid syndrome. Severe respiratory insufficiency treated with CPAP]. / Sindrome da acido retinoico: grave insufficienza respiratoria trattata con ventilazione in maschera con CPAP.

Retinoic acid syndrome is a potentially life-threatening complication of therapy for acute promyelocytic leukemia (APL) with all-transretinoic acid (ATRA). The case of a 55-year old male patient admitted to the hospital because of a bleeding diathesis is reported. APL was diagnosed and he underwent treatment with idarubicin and ATRA (GIMEMA protocol); 24 hrs after ATRA treatment he developed retinoic acid syndrome and was admitted to the Intensive Care Unit because of severe respiratory insufficiency (dyspnoea, tachypnea and severe hypoxemia (SpO2 75%). Pulmonary insufficiency was treated non-invasively with CPAP and the patient recovered from pulmonary distress one week later.

Customization of SAPS II for the assessment of severity in Italian ICU patients. ARCHIDIA. Archivio Diagnostico.

BACKGROUND: To assess the accuracy of SAPS II on the Italian population and to perform a customization of the model. DESIGN: observational prospective study. PATIENTS: 24 participating centers. 6794 patients out of 9185 enrolled in the cohort study. MEASUREMENTS: the performance of SAPS II was assessed with calibration and discrimination. In the case of standard model not fitting the data, new logistic regression equation has been calculated using Archidia database. RESULTS: SAPS II showed a good discrimination, but a bad calibration. The new logit has been calculated on the population examined in 1995 and successively tested on the population collected during 1996. In both samples discrimination and calibration results were good. CONCLUSIONS: Our customized model reaches a high standard in calibration and discrimination. We suggest this model for future application in Italian ICU.

Combined treatment of Dunning R3327 rat prostatic tumor with the 5alpha-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide.

UNLABELLED: PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenyl-propyl)-3-oxo-4-aza- 5alpha-androst-1-ene-17beta-carboxamide], a novel, potent and selective dual 5alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. PURPOSE: We investigated the efficacy of treatment with PNU 157706 in combination with the antiandrogen bicalutamide in this prostatic tumor model. METHODS: Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.2 and 1 mg kg per day). Animals were killed 24 h after the last treatment, and ventral prostates were removed for testosterone (T) and dihydrotestosterone (DHT) determination. RESULTS: PNU 157706 reduced the growth of established tumors by 39%; bicalutamide proved ineffective at 0.2 mg/kg per day, but reduced tumor growth by 45% at a dose of 1 mg/kg per day. The combination of PNU 157706 with both doses of bicalutamide caused an additive tumor growth inhibition (50% and 64%). Castration resulted in marked tumor growth inhibition (72%). Ventral prostate weight was markedly reduced by PNU 157706 (78%) treatment and by bicalutamide (59% and 77%); combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (88%), whereas prostatic T increased slightly (60%). Concomitant treatment with bicalutamide antagonized the T increase induced by PNU 157706 and did not modify the already remarkable suppression of DHT. CONCLUSIONS: These data show that the inhibitory effect of PNU 157706 and bicalutamide on Dunning prostatic tumor growth is additive, thus suggesting a possible role of PNU 157706 in the therapy of advanced prostate cancer, in combination with antiandrogens, to provide an effective peripheral androgen ablation therapy with minimal side effects.

Patient survival and cardiovascular events after kidney-pancreas transplantation: comparison with kidney transplantation alone in uremic IDDM patients.

In diabetic patients cardiovascular morbidity and mortality is still a major problem. Our aim was to study the effect of kidney-pancreas transplantation on survival, cardiovascular events, and causes of death in diabetic type 1 uremic patients. Three hundred and thirty-three uremic IDDM patients were enrolled in our waiting list for kidney-pancreas transplantation: 107 underwent kidney-pancreas transplantation (KP), 34 underwent kidney transplantation alone (KA), whereas 192 patients remained on dialysis (WL). Actuarial survival and causes of death were recorded over a period of 7 years. Seven-year survival rate was 75% for the KP group, 63% for the KA group, and 37% for the WL group (p = 0.001). Cardiovascular death rate was 9.8% in the KP group, 17.6% in the KA group, and 18.1% in the WL group (KP vs. WL, p = 0.05). Rate of acute myocardial infarction in the KP group was lower than in the KA group (2.4% vs. 17.6%, p = 0.005) as well as rate of acute pulmonary edema (0.8% vs. 23.5%, p = 0.0001) and rate of hypertensive patients at 1 (40.9% vs. 85.0%, p = 0.0001) and at 2 years (57.6% vs. 80%, p = 0.03). Kidney-pancreas transplant helped to obtain euglycemia with positive effects on survival and cardiovascular events.

Combined treatment with the 5 alpha-reductase inhibitor PNU 157706 and the antiandrogen flutamide on the Dunning R3327 prostatic carcinoma in rats.

The steroid 5 alpha-reductase enzyme catalyzes the conversion of testosterone to the potent androgen 5 alpha-dihydrotestosterone (DHT). PNU 157706, a novel, potent and selective dual 5 alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We have studied the efficacy of combined treatment with PNU 157706 and the antiandrogen flutamide in this prostatic tumor in rats. Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with flutamide (1 and 5 mg/kg per day). Animals were killed 24 h after the last treatment and ventral prostates were removed for testosterone and DHT determination. PNU 157706 reduced the growth of established tumors by 36%; flutamide showed a slight effect at 1 mg/kg per day (24% inhibition), while at the dose of 5 mg/kg per day it reduced tumor growth by 48%. The combination of PNU 157706 with the lower dose of flutamide caused an additive tumor growth inhibition (60%) and the combination with the higher dose of flutamide resulted in a better inhibition of tumor growth (68%) than did either treatment alone. Castration resulted in marked tumor growth inhibition (76%). Ventral prostate weight was more markedly reduced by PNU 157706 treatment than by flutamide; combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (93%), whereas prostatic testosterone increased (137%). Concomitant treatment with flutamide partially antagonized the testosterone increase induced by PNU 157706 and did not modify the already considerable suppression of DHT. These data show that the inhibitory effects of PNU 157706 and flutamide on Dunning prostatic tumor growth are additive, thus supporting the rationale of this combination therapy in advanced prostate cancer, in order to achieve adequate androgen blockade with minimal side-effects.

[Percutaneous or surgical trachetomy. Prospective, randomized comparison of the incidence of early and late complications]. / Tracheotomia percutanea e chirurgica. Confronto prospettico, randomizzato dell'incidenza di complicanze precoci e tardive.

BACKGROUND: To compare early and late complications after either conventional surgical or percutaneous dilatational tracheostomy. DESIGN: Prospective, randomized study. SETTING: General intensive care unit and neuro-surgical intensive care unit in a university hospital. PATIENTS: 50 consecutive patients, requiring tracheostomy for prolonged mechanical ventilation. INTERVENTIONS AND MEASUREMENTS: Patients were randomly allocated to receive either surgical (surgical group, n = 25) or percutaneous dilatational tracheostomy (percutaneous group, n = 25). Occurrence of perioperative complication were carefully evaluated during ICU stay. Late complications were evaluated with both physical and endoscopic examination at 1, 3 to 6 months after tracheostomy. RESULTS: All surgical and percutaneous tracheostomies were successfully completed and no deaths directly related to the tracheostomy procedures were reported. Completion of the procedure required 41 +/- 14 min in the surgical group and 14 +/- 6 min in the percutaneous one (p < 0.0001). The incidence of early perioperative complications was higher in the surgical group (36%) than in percutaneous one (12%), (p < 0.05). The endoscopic follow-up demonstrated one segmental malacia and one stenosis of the trachea in the percutaneous group only (p = n.s.). Skin repair was better after percutaneous tracheostomy than in the surgical group (p < 0.01). CONCLUSIONS: In experienced hands, percutaneous dilatational tracheostomy is as safe and effective as the conventional surgical tracheostomy. The percutaneous technique is less time-consuming and has a lower rate of early infectious complications with better cosmetic results than the surgical technique.

Antithrombin replacement in patients with sepsis and septic shock.

Sepsis is a frequent complication of critically ill patients and its incidence is increasing. Currently, septic shock is the most common cause of death in non-coronary intensive care units. Over the last 10 to 15 years, new antibiotics and increasingly sophisticated critical care have had little impact on the mortality rate of septic shock. The Italian SEPSIS Study, carried out in 99 intensive care units in 1994, reported mortality rates of 52% and 82% for severe sepsis and septic shock respectively. New therapeutic approaches aimed at neutralizing microbial toxins and modulating host mediators have shown some efficacy in large clinical trials and/or in animal models, but to date, no therapy of sepsis aimed at reversing the effects of bacterial toxins or of harmful endogenous mediators of inflammation has gained widespread clinical acceptance. Because of the strong association of severe sepsis with a state of activation of blood coagulation and of the potential role of capillary thrombosis in the development of the multiple organ dysfunction syndrome, anticoagulant agents have been tested in the setting of septic shock. However, neither administration of heparin nor of active site-blocked factor Xa or of anti-tissue factor antibodies have proven effective in preventing deaths due to septic shock in animal models. In contrast, infusion of antithrombin, protein C, or tissue factor pathway inhibitor all resulted in a significant survival advantage in animals receiving lethal doses of E. Coli. Antithrombin concentrates have been used in a significant number of critically ill patients. A double-blind, placebo controlled study carried out in 3 italian intensive care units has recently shown that the administration of antithrombin aimed to normalize plasma antithrombin activity had a net beneficial effect on 30-day survival of patients requiring respiratory and/or hemodynamic support because of severe sepsis and/or post-surgery complications.

Mono-oligoclonal immunoglobulin abnormalities in diabetic patients after kidney transplantation: influence of simultaneous pancreas graft.

Monoclonal components (MC) are detected in as high as 30% of renal transplant recipients. Our aim was to evaluate the incidence, relevance and consequence of monoclonal components in patients with Type I (insulin-dependent) diabetes who received kidney (n = 22), kidney and whole pancreas (n = 41), kidney and segmental pancreas (n = 24) and kidney and islets (n = 12) transplants. Immuno-suppression was based on prophylactic anti-lymphocyte globulins, corticosteroids, azathioprine and cyclosporin in all patients; acute rejection was treated with steroids or anti-lymphocyte monoclonal immunoglobulin therapy (OKT3) or both. Serum immunofixation was carried out in all patients before transplantation and then after at 6 months and then yearly. Monoclonal components were detected in 81 of 99 patients (82%); 52 patients (52%) developed them within 6 months of transplantation, 15 (15%) between 6 and 12 months, with a peak prevalence at 1 year post-transplant (58%) and a decrease thereafter (10% at 9 years). Kidney recipients showed a lower incidence of monoclonal components when compared with those who received kidneys and segmental pancreases and those who received kidneys and whole pancreases. Monoclonal components were more often detected in patients who had previously experienced an acute renal rejection. Cytomegalovirus infection and acute rejection occurring in the same patient further increased the risk of developing monoclonal components, the development of which did not correlate with OKT3 treatment. A Post-transplant lymphoproliferative disorder was developed by two patients (2%), one with 5 and the other with 6 monoclonal components. In conclusion, diabetic patients receiving kidney and/or Pancreas transplantation, experiencing both cytomegalovirus infection and acute rejection, are at greatest risk of developing monoclonal components but they appear to be benign and transient; multiple band detection is a marker for the subsequent development of post-transplant lymphoproliferative disorder.

Effect of the 5 alpha-reductase inhibitor PNU 156765, alone or in combination with flutamide, in the Dunning R3327 prostatic carcinoma model in rats.

The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49-50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5 alpha-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.

Effect of early treatment of prostate cancer with the 5alpha-reductase inhibitor turosteride in Dunning R3327 prostatic carcinoma in rats.

BACKGROUND: Turosteride, a selective 5alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model. We evaluated the preventive effect of turosteride when administered during the latency period in this prostatic tumor model. METHODS: Turosteride was given orally, 6 days a week for 10-15 weeks, starting at different times: 1) 5 weeks after tumor implantation, when tumors were not yet palpable, or 2) 1 day after tumor implantation. In each experiment, one group of animals was castrated on the first treatment day. RESULTS: When treatment started 5 weeks after tumor implantation, neither turosteride (at 50 and 200 mg/kg/day) nor castration reduced tumor incidence (91-100%). Tumor growth was reduced in groups treated with the highest dose of turosteride and in castrated rats. When treatment started 1 day after tumor implantation, castration resulted in a 62% tumor incidence compared to 100% in controls, while turosteride at 200 mg/kg/day was not effective in reducing tumor incidence. However, as in the previous experiment, the compound was highly effective in reducing tumor growth. CONCLUSIONS: The antitumor activity profile of turosteride seems not to be related to the timing of treatment. Given either 5 weeks or 1 day after tumor implantation, the compound did not reduce tumor take, while it maintained effective tumor growth-inhibiting activity in both cases.

Antithrombin III (ATIII) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study.

BACKGROUND: ATIII is decreased in sepsis and/or shock and its baseline value correlates with mortality. The efficacy of ATIII therapy on mortality was assessed in a selected group of patients admitted to the intensive care unit (ICU) in a double-blind, randomized, multicenter study. METHODS: 120 patients admitted to the ICU with an ATIII concentration < 70% were randomized to receive ATIII (total dose 24000 units) or placebo treatment for 5 days; 56 patients had septic shock. RESULTS: ATIII concentrations in the treated group remained constant throughout the treatment period (range 97-102%). The Kaplan-Meier analysis showed no difference in overall survival between the two groups: 50 and 46% for ATIII and placebo, respectively. Septic shock and hemodynamic support were unbalanced in the two groups at admission. Therefore the Cox analysis was carried out after adjusting for these two variables. Treatment with ATIII decreases the risk of death with an odds ratio (OR) of 0.56. Of the covariates analyzed, septic shock and the baseline multiple organ failure score were negatively associated with survival and plasma activity level was positively associated with survival with an OR of 0.97 for each 1% increase in the ATIII plasma concentration at baseline. CONCLUSIONS: The results of ATIII treatment in this population of patients suggests that replacement therapy reduces mortality in the subgroup of septic shock patients only.

PNU 157706, a novel dual type I and II 5alpha-reductase inhibitor.

PNU 157706 is a novel dual inhibitor of 5alpha-reductase (5alpha-R), the enzyme responsible for the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). Tested on a crude preparation of human or rat prostatic 5alpha-R, PNU 157706 caused enzyme inhibition with IC50 values of 20 and 34 nM, respectively, compared to the values of 32 and 58 nM shown by finasteride. Furthermore, PNU 157706 was highly potent in inhibiting human recombinant 5alpha-R type I and II isozymes, showing IC50 values of 3.9 and 1.8 nM and, therefore, it was several folds more potent than finasteride (IC50 values of 313 and 11.3 nM), particularly on the type I isozyme. PNU 157706 was shown to have no binding affinity for the rat prostate androgen receptor (RBA 0.009% that of DHT). In adult male rats, a single oral dose of 10 mg/kg of PNU 157706 caused a marked and longer lasting reduction of prostatic DHT than did finasteride (at 24 h inhibition by 89 and 47%, respectively). In prepubertal, T- or DHT-implanted castrated rats, PNU 157706, given orally for 7 days at the dose of 10 mg/kg/day, markedly reduced ventral prostate weight in T- but not in DHT-implanted animals, thus showing to be devoid of any anti-androgen activity. In adult rats treated orally for 28 days, PNU 157706 resulted markedly more potent (16-fold) than finasteride in reducing prostate weight, the ED50 values being 0.12 and 1.9 mg/kg/day, respectively. These results indicate that PNU 157706 is a promising, potent inhibitor of both type II and I human 5alpha-R with a very marked antiprostatic effect in the rat.

Effect of the dual 5alpha-reductase inhibitor PNU 157706 on the growth of dunning R3327 prostatic carcinoma in the rat.

PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenylpropyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide] is a novel, potent and selective dual 5alpha-reductase inhibitor. We have investigated its effect on tumor growth, endocrine organ weights and prostatic dihydrotestosterone (DHT) content in rats bearing the androgen dependent Dunning R3327 prostatic carcinoma. Animals with tumor diameters of about 1 cm were treated orally for 9 weeks with PNU 157706 (2 and 10 mg/kg/day, 6 days a week) or they were castrated, to check the hormone responsiveness of the tumor. PNU 157706 was effective at both doses tested in reducing tumor growth (53 and 51% inhibition at 2 and 10 mg/kg/day, respectively), while castration caused higher inhibition (82%) of tumor growth. A marked reduction of ventral prostate weight occurred in rats treated with both doses of PNU 157706 (75 and 78%) or castrated (91%). Seminal vesicle weight was also reduced by PNU 157706 administration (56 and 61% inhibition), whereas testes, adrenal, thymus and pituitary weights were not affected. Prostatic DHT content was markedly suppressed (85 and 91%) in PNU 157706 treated rats, compared to 95% suppression caused by castration. These data support a possible role of dual 5alpha-reductase inhibitors in the hormonal therapy of prostatic cancer.