QTc interval diurnal variations in patients treated with psychotropic medications: implications for the evaluation of drug induced QTc changes.

Psychotropic drugs such as antipsychotics may prolong the QTc interval, increasing the risk of torsades de pointes (TdP) and sudden cardiac death. To assess QTc prolongation by psychotropic drugs, an electrocardiogram (EKG) is usually recorded before and after starting treatment. Circadian variations in the QTc interval have been described but have not been adequately studied in patients taking psychotropic drugs. In psychiatric clinical practice, EKGs before and after treatment initiation are often compared, without considering the time of day at which the two EKGs are recorded. To determine whether there is a circadian change in the QTc interval in patients treated with psychotropic drugs, we evaluated the EKGs of a group of patients treated with psychotropic drugs (85% on antipsychotics) and the EKGs of a group of patients that were not treated with medications. In each group, we compared the EKGs recorded before 11:00 am with those recorded after 5:00 pm. The QTc value was significantly longer in the group treated with psychotropic drugs than in the group without drugs at both morning and evening evaluations (p ≤ 0.001). In each group, a statistically significant difference was found between the EKGs recorded before 11:00 a.m. and the EKGs recorded after 5:00 p.m. In patients treated with medications, the mean QTc in the morning was 453.3 ± 25.4 while the mean QTc in the afternoon was 428.4 ± 24.7 (p < 0.0001). In patients who were not receiving any medication, the morning mean QTc was 422.4 ± 22.6 while the mean afternoon QTc was 409.4 ± 19.6 (p = 0.002). These results suggest that a circadian variation in QTc is observed both in patients taking psychotropic drugs and in patients not taking medication. We conclude that any comparison of EKGs to test the effect on QTc of a medication, should be referred to EKGs recorded at the same time of day.

Premorbid academic and social functioning in patients with schizophrenia and its associations with negative symptoms and cognition.

OBJECTIVE: The study aimed to explore premorbid academic and social functioning in patients with schizophrenia, and its associations with the severity of negative symptoms and neurocognitive impairment. METHOD: Premorbid adjustment (PA) in patients with schizophrenia was compared to early adjustment in unaffected first-degree relatives and healthy controls. Its associations with psychopathology, cognition, and real-life functioning were investigated. The associations of PA with primary negative symptoms and their two factors were explored. RESULTS: We found an impairment of academic and social PA in patients (P ≤ 0.000001) and an impairment of academic aspects of early adjustment in relatives (P ≤ 0.01). Patients with poor PA showed greater severity of negative symptoms (limited to avolition after excluding the effect of depression/parkinsonism), working memory, social cognition, and real-life functioning (P ≤ 0.01 to ≤0.000001). Worse academic and social PA were associated with greater severity of psychopathology, cognitive impairment, and real-life functioning impairment (P ≤ 0.000001). Regression analyses showed that worse PA in the academic domain was mainly associated to the impairment of working memory, whereas worse PA in the social domain to avolition (P ≤ 0.000001). CONCLUSION: Our findings suggest that poor early adjustment may represent a marker of vulnerability to schizophrenia and highlight the need for preventive/early interventions based on psychosocial and/or cognitive programs.

Copeptin: a blood test marker of syncope.

AIMS: Copeptin (CPT) is regarded as a stress hormone, and as a novel marker of acute disease, and it has never been tested for a role in diagnosing syncope. The main objectives of the study were to measure CPT in patients suffering from syncope, to determine its diagnostic sensitivity and specificity, and compare it with that in patients with falls and mild trauma. The secondary objective was to determine whether different types of syncope correlate with different levels of CPT. METHODS: Fifty-one patients suffering from syncope and 51 suffering from falls without syncope were included in this study. Patients with a diagnosis of acute comorbidity were excluded. The diagnostic work was in accordance with the Guidelines of the European Cardiology Society. The level of CPT was measured in each patient evaluating the mean values in syncope vs. falls and in the different syncope type and the values over or under the normal threshold. RESULTS: Of the 51 patients with syncope, 44 had abnormal and 7 normal CPT levels. Of the 51 patients with falls, 47 had normal and 4 abnormal levels of CPT. There was no difference in mean CPT levels in patients with different types of syncope. There was no correlation between levels of CPT and age or sex. There was a relationship between normal CPT levels and falls. CONCLUSION: Copeptin is an efficient marker of syncope. It is useful for confirming or ruling out a diagnosis of syncope in patients who are unable to provide a definite history or when the event is unwitnessed.

Breakthrough pain in patients with multiple myeloma: a secondary analysis of IOPS MS study.

OBJECTIVE: The aim of this study was to characterize breakthrough pain (BTcP) in patients with multiple myeloma (MM). PATIENTS AND METHODS: This was a secondary analysis of a large multicenter study of patients with BTcP. Background pain intensity and opioid doses were recorded. The BTcP characteristics, including the number of BTcP episodes, intensity, onset, duration, predictability, and interference with daily activities were recorded. Opioids prescribed for BTcP, time to achieve a meaningful pain relief after taking a medication, adverse effects, and patients' satisfaction were assessed. RESULTS: Fifty-four patients with MM were examined. In comparison with other tumors, in patients with MM BTcP was more predictable (p=0.04), with the predominant trigger being the physical activity (p<0.001). Other BTcP characteristics, pattern of opioids used for background pain and BTcP, satisfaction and adverse effects did not differ. CONCLUSIONS: Patients with MM have their own peculiarities. Given the peculiar involvement of the skeleton, BTcP was highly predictable and triggered by movement.

Superomedial pedicle skin-reducing mastectomy in ptotic and large-sized breasts with two-stage reconstruction through transaxillary video-assisted technique: An effective surgical and anesthetic approach.

Introduction: Skin-reducing mastectomy has been applied to several surgical techniques in which subcutaneous mastectomy is associated with various types of skin reduction, with preservation of a lower dermal flap to reinforce the inferior lateral seat of an implant. The aim of the study is to present a case series of patients with pendulous/ptotic and/or large-sized breasts treated for breast cancer at the Breast Surgery Unit of Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Naples, Italy, with the superomedial pedicle skin-reducing mastectomy technique, two-stage reconstruction, and transaxillary video-assisted technique, when a postoperative radiotherapy was indicated. We verified its effectiveness by discussing its results, especially in patients who are candidates for postmastectomy radiotherapy. Materials and methods: A single-center retrospective study was performed between January 2020 and March 2021 on a prospectively filled database of conservative mastectomies. Of the 64 patients who underwent nipple/skin-sparing mastectomies in the mentioned period, 17 (mean age 46 years, range 30-62 years) were treated with superomedial pedicle skin-reducing mastectomy, with two-stage breast reconstruction through transaxillary video-assisted replacement expander with definitive prosthesis and contralateral symmetrization, selected for postmastectomy radiotherapy. Results: We had only three minor complications. No flap necrosis, no infections, no breast seromas, and no reconstructive failures were observed. During follow-up of the patients treated with video-assisted reconstruction, there were no cases of infection, hematoma, implant rupture, or suture dehiscence in the reconstructed breast. Discussion: Skin-reducing mastectomy with superomedial pedicle is a safe and reliable procedure to treat breast cancer in selected patients, i.e., those with pendulous/ptotic and or large-sized breasts. Particularly, in patients who undergo postmastectomy radiotherapy, the two-stage reconstruction with video-assisted transaxillary endoscopic approach can find its main indication, using incisions positioned far from the mammary region, offering numerous advantages.

Efficacy of ustekinumab in the treatment of patients with Crohn's disease with failure to previous conventional or biologic therapy: a prospective observational real-life study.

Ustekinumab (UST), a human anti-IL12/23p40 monoclonal antibody, was approved by FDA and EMA for the treatment of moderate to severe Crohn's disease (CD). Whether UST is effective in inducing deep remission, including mucosal healing and transmural healing, in patients with CD in a real life setting is not completely clear. This study was performed on 92 subjects with confirmed diagnosis of moderate to severe Crohn's disease and no neoplasia. Before inclusion, all patients had been exposed and had failed to respond to conventional and/or at least one biological therapy. All patients underwent endoscopic examination and bowel MRI and ultrasonography at baseline (T0). At week 52 (T52), patients underwent colonoscopy for assessment of mucosal healing and MRI or ultrasonography for assessment of transmural healing. CDAI was used for the assessment of clinical response and clinical remission. SES-CD was used to assess endoscopic response and remission. Incidence of treatment-related adverse events (TRAEs) was recorded during the study period. Clinical response at week 52 was achieved in 38 (50.5%) patients and clinical remission in 29 (39%). Twenty-six (34%) patients showed mucosal healing, 34 (45%) showed partial endoscopic response. We observed a reduction in SES-CD of at least 50% in 34 (45%) patients as well as an SES-CD ≤ 2 in 26 (35%) patients. All patients with mucosal healing also showed transmural healing. No major TRAEs were observed during treatment. In this multicenter, real life study, we show that UST was well tolerated and effective in inducing clinical response and clinical remission in patients with moderate to severe CD who had previously failed to respond to conventional or biologic therapy. UST showed limited efficacy in inducing deep remission (i.e. mucosal+transmural healing).

Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Multiple effectiveness aspects of tapentadol for moderate-severe cancer-pain treatment: an observational prospective study.

BACKGROUND: Previous studies have shown the efficacy of tapentadol (TP) for chronic cancer pain. We evaluated multiple effectiveness aspects of TP prolonged release on moderate-severe cancer-related pain, neuropathic pain (NeP), patient satisfaction, and quality of life. METHODS: An observational prospective study was conducted on 80 cancer patients. Opioid-naïve patients received a starting dose of prolonged-release TP 50 mg twice daily, and opioid-experienced patients were switched to TP, not to exceed 500 mg/day. Treatment response was evaluated at 3, 6, 30-40, and 60-70 days through response rate, numeric rating-scale scoring, survival analysis (time to event for response), pain-intensity difference, TP escalation-index percentage, and effects on NeP. The drug-sparing effect on concomitant therapies was evaluated. RESULTS: Seventy of 80 patients (88%) were responders to treatment (95% CI 78%-94%). Compared to T0, pain-intensity reductions were statistically significant for all intervals (P<0.01), with better results at T3/T4. NeP was significantly reduced at T4 (P<0.01). The probability of response was low at the initial stages and increased during the study. Pain-intensity differences decreased during the study, though without significance. Two patients (2.5%) left the study for TP-induced side effects. A significant improvement in quality of life was observed after 30-40 days (P<0.01). The majority of patients were "satisfied", "very satisfied", or "extremely satisfied" (T3-T4). CONCLUSION: TP was effective in terms of drug-sparing effect, response rate, TP escalation-index percentage, and NeP management. By comparing data from the survival analysis with the response rate and time to response (numeric rating scale from T0 to T4), we found that although TP induced a quick response, a longer period of therapy and higher doses were needed to improve the positive result.

Aripiprazole use during pregnancy, peripartum and lactation. A systematic literature search and review to inform clinical practice.

BACKGROUND: Aripiprazole is used relatively frequently in women with bipolar disorder or schizophrenia in childbearing years, owing to its efficacy and relatively favorable side effect profile. As is the case for other psychotropic medications, for ethical reasons, no prospective randomized placebo controlled trial to assess aripiprazole safety during pregnancy has ever been conducted. However, animal data are available and the amount of exposure and outcome data for human fetuses and infants has recently increased, providing published prospective safety data in relatively large numbers of pregnant women treated with aripiprazole. The aim of this study was to perform a systematic literature search and review to critically evaluate the available data on the use of aripiprazole during pregnancy, peripartum and lactation. METHODS: PubMed, PsychInfo, and Cochrane Library were searched using the following search builder: (pregnancy OR pregnant OR gestation OR malformations OR perinatal OR reproduction OR organogenesis OR delivery OR breast-feeding OR lactation or peripartum or obstetric) AND aripiprazole. Reports that met the following pre-defined criteria were included in the present review: (1) published in English language in a peer-reviewed journal; (2) clearly defined use of aripiprazole during pregnancy and/or lactation and/or postpartum; (3) case report, case series, prospective, retrospective or cross-sectional studies. United States and European Medicine Agency prescribing information for aripiprazole were consulted as well and all the references of selected papers were cross checked for information pertaining to the use of aripiprazole during pregnancy, peripartum and lactation. RESULTS: A total of 549 items published in a period ranging from 1995 to 2017, were retrieved from the search databases and reference cross check. One-hundred-fifty-three duplicate items were removed, 176 titles were deemed as not pertinent, 220 abstracts and 122 full-text articles were assessed for eligibility and 93 titles were included for qualitative synthesis. United States and European Medicine Agency prescribing information for aripiprazole were consulted and the selected manuscript references were cross checked. No randomized placebo controlled trial was found but relatively large prospective studies, large database studies, and several case reports and case studies were identified and summarized. CONCLUSIONS: As is the case for other antipsychotics, definitive evidence on aripiprazole reproductive safety is lacking, but newer safety data are relatively reassuring. In many cases, the potential benefits of aripiprazole for patients with bipolar disorder or schizophrenia outweigh the potential risks.

Disorganization and real-world functioning in schizophrenia: Results from the multicenter study of the Italian Network for Research on Psychoses.

BACKGROUND: A general consensus has not yet been reached regarding the role of disorganization symptoms in real-world functioning in schizophrenia. METHODS: We used structural equations modeling (SEM) to analyze the direct and indirect associations between disorganization and real-world functioning assessed through the Specific Levels of Functioning Scale (SLOF) in 880 subjects with schizophrenia. RESULTS: We found that: 1) conceptual disorganization was directly and strongly connected with SLOF daily activities; difficulty in abstract thinking was associated with moderate strength to all SLOF domains, and poor attention was connected with SLOF work skills; 2) grandiosity was only related with poor work skills, and delusions were associated with poor functioning in all SLOF domains; interpersonal relationships were weakly indirectly influenced by hallucinatory behavior, delusions and unusual thought contents through the mediation of social cognition (SC); 3) among the negative symptoms, avolition had only direct links with SLOF work skills and SLOF activities; anhedonia had direct links with SLOF work skills and SLOF interpersonal and indirect link with SLOF work skills through functional capacity (FC); asociality with SLOF interpersonal; blunted affect had direct links with SLOF activities and indirect links with SLOF interpersonal relationships mediated by SC. Lastly, alogia had only indirect links mediated by SC, FC, and neurocognition (NC). CONCLUSIONS: Overall conceptual disorganization is the symptom that contributed more (both directly and indirectly) to the activities of community living in real-world. Thus, it should be considered as a treatment target in intervention programs for patients with schizophrenia.

Periprocedural management of antithrombotic therapy and open issues in cancer patients.

Perioperative management of patients who are receiving anticoagulant or antiplatelet drugs and require surgical or invasive procedure is a dilemma for clinicians. The discontinuation exposes the patient to an exceedingly high risk of thromboembolism while there is an exceedingly high bleeding risk if antithrombotic therapy is continued, strictly related to the type of surgery. This complex management is based on the assessment of thromboembolic and bleeding risk. In this review we analyze the strategies to optimize the perioperative use of antithrombotic drugs with special attention to new oral anticoagulant drugs, also in cancer patients.

Provocative dose and dose-response curve to inhaled propranolol in asthmatic patients with bronchial hyperresponsiveness to methacholine.

This study was carried out to compare bronchial responses to inhaled propranolol (P) and methacholine (M) in a group of asthmatic subjects with mild to moderate bronchial hyperresponsiveness to M; to determine the short term reproducibility of bronchial response to propranolol; and to examine the shape of dose-response curve to P relative to that of M. Doses of M and P were given in mumoles and bronchial responses to both agents were expressed as the provocative dose that induced a 20 percent fall in FEV1 (PD20 FEV1). In 16 asthmatic patients, there was no correlation between the PD20 of the two agents. Mean PD20 M (+/- SD in log scale) was approximately nine times lower than mean PD20 P (0.64 +/- 0.96 and 5.80 +/- 1.65, respectively). This difference was statistically significant (t = 4.58, p less than 0.001). In six asthmatic patients, the reproducibility of PD20 P was similar to that of M (intraclass correlation coefficient 0.969 and 0.957, respectively). The shape of the dose-response curves to P was different from that of M in five of nine asthmatic patients when all experimental points were analyzed by double-reciprocal plot. We noticed that even small doses of inhaled P may cause a severe bronchoconstriction. Therefore, special caution should be taken to increase P doses very gradually, when studying the dose-response curve. We demonstrated that P inhalation induced a measurable bronchoconstriction in subjects with mild to moderate hyperresponsiveness and it was reproducible. However, the bronchial sensitivity to P was lower than to M. Our findings suggest that P and M have different mechanisms of action.

Inhaled corticosteroids in stable COPD patients: do they have effects on cells and molecular mediators of airway inflammation?

STUDY OBJECTIVE: To investigate possible changes in cells and molecular mediators of airway inflammation following inhaled steroid treatment of stable COPD patients. DESIGN: Six-week open preliminary prospective study. SETTING: A university respiratory disease clinic. PATIENTS: : Stable COPD patients with mild disease. INTERVENTION: Six-week treatment with inhaled beclomethasone (1.5 mg die). MEASUREMENTS: The levels of interleukin (IL)-8, myeloperoxidase, eosinophilic cationic protein and tryptase, and cell numbers in bronchial lavage specimens were determined, and the symptom score, the endoscopic bronchitis index, and functional parameters were recorded. RESULTS: After treatment there were significant reductions in the lavage levels of IL-8 ([mean +/- SEM] 1,603.4 +/- 331.2 vs 1,119.2 +/- 265.3 pg/mL, respectively; p = 0. 01) and myeloperoxidase (1,614.5 +/- 682.3 vs 511.2 +/- 144.2 microg/L, respectively; p = 0.05), in cell numbers (250.6 +/- 27.7 vs 186.3 +/- 11.5 cells x 10(3)/mL, respectively; p = 0.04), neutrophil proportion (59.7 +/- 14.3% vs 31.5 +/- 10.1%; p = 0.01), symptom score (4.5 +/- 0.6 vs 1.4 +/- 0.5; p = 0.01), and bronchitis index (8.5 +/- 0.8 vs 5.5 +/- 0.7; p = 0.007). CONCLUSIONS: In stable patients with COPD, inhaled steroid treatment may induce changes on some cellular and molecular parameters of airway inflammation.

Hematopoietic stem cells from different sources: biological and technical aspects.

Hematopoietic stem cell (HSC) enumeration is crucial to predict the engraftment potential of a given HSC collection, and currently involves the surrogate count of nucleated cells, CFU or CD34+ cells. However, there is raising evidence that CFU are HSC involved in short-term but not in long-term reconstitution, and that only a small fraction of all CD34+ cells have long term multilineage engraftment potential. In this regard, there is evidence that cord blood (CB), bone marrow (BM) and peripheral blood (PB) derived HSC are highly heterogeneous for a number of antigens useful for HSC enumeration by flow cytometry. Moreover, there is a raising evidence that a CD34 human HSC might exist. The CD34 HSC has been already described in animals and in human Hoechst 33342 negative HSC. This notwithstanding, clinical data have clearly demonstrated that purified allogeneic CD34+ cells can reconstitute the myeloid and the lymphoid lineages in myeloablated recipients. In the lack of a suitable marker for CD34 HSC enumeration, it is hard to predict the role of CD34 HSC in hematopoietic reconstitution after transplantation. On the other hand, these cells might be a better target for HSC expansion and gene transfer.

Role of tumor cells contaminating the graft in breast cancer recurrence after high-dose chemotherapy.

One of the possible drawbacks to autologous stem cell transplantation in breast cancer (BC) patients is the potential for tumor contamination in the transplanted product. We present a patient with advanced disease who received high-dose chemotherapy (HDC) and PBPC support as consolidation therapy after achieving complete remission with standard-dose first-line treatment, and suffered recurrence of the disease 6 months after transplantation. Retrospective analysis revealed the presence of contaminating cells in the leukapheretic product, and clinical evidence suggested a role for these cells in the tumor relapse.

Clinical toxicity of cryopreserved circulating progenitor cells infusion.

BACKGROUND: We evaluated the infusion-related toxicity of cryopreserved autologous circulating progenitor cells transplanted in 22 patients receiving high dose chemotherapy and stem cells transplantation for malignancy. MATERIALS AND METHODS: Progenitor cells were collected following mobilization with chemotherapy plus filgrastim and stored in liquid nitrogen in the presence of 10% dimethylsulfoxide (DMSO). Before infusion of the graft, patients were medicated with mannitol, hydrocortisone and clorphenamine. The amount of DMSO infused as well as the number of dead and damaged cells were evaluated as possible cause of toxicity. RESULTS: Eleven patients (50%) experienced symptoms related to graft infusion, nausea and vomiting being the most common adverse events. Hypotension was documented in 3 patients (one of them developing transient bradycardia resolved with atropin administration) and one had hypertension with tachycardia. Other observed side effects were: chest tightness (2 pts), fever and chills (3 pts), associated with abdominal cramps (2 pts). 7 out of 8 (88%) patients infused with greater than 30 mL volume of DMSO experienced side-effects, the grade of toxicity being significantly less in those receiving lower amount (< 30 mL) of DMSO. Two out of 4 pts who received the highest number of dead cells (> 10 x 10(9)) developed toxicity. CONCLUSIONS: In our experience the infusion of cryopreserved peripheral blood progenitors caused minor to moderate toxicity in most cases and, when present, side effects were observed only during infusion. The amount of DMSO present in the graft is related to the grade of toxicity.

Neutrophils infiltrating bronchial epithelium in chronic obstructive pulmonary disease.

In order to characterize neutrophil and eosinophil presence in the airways of patients with chronic obstructive pulmonary disease (COPD), bronchoscopy with bronchial washings and bronchial biopsies was performed in 12 smoking stable COPD subjects and 18 normal non-smoking control subjects. Bronchial biopsies were examined by light microscopy using plastic embedding and histochemical techniques to identify different cell types. Bronchial washing fluid of COPD patients was characterized by a predominance of neutrophils (P = 0.001), and a slight, but significant (P = 0.03), increase of eosinophil fraction. Subjects with COPD had higher number of neutrophils in the epithelium (P = 0.01), and eosinophils in the lamina propria (P = 0.01) than did control subjects. The thickness of reticular basement membrane was increased for COPD patients in comparison to control subjects (P = 0.01). The present study provides evidence of neutrophil infiltration both in bronchial washing and bronchial epithelium of patients with COPD, suggesting that the source of neutrophils in airway lumen may be the bronchial mucosa. Although less common than in asthma, airways of COPD subjects reveal eosinophil presence and airway remodelling.

Phase II study with ifosfamide, carboplatin, etoposide (ICE regimen) at intermediate dosage for advanced non small cell lung cancer (NSCLC).

We have evaluated the combination of ifosfamide, carboplatin and etoposide (ICE regimen) along with mesna in 26 previously untreated patients with non small cell lung cancer (NSCLC). Thirteen stage III B and 13 stage IV patients received intermediate doses of ifosfamide (1000 mg/m2), carboplatin (120 mg/m2) and etoposide (120 mg/m2) given intravenously on day 1 to 3 every 4 weeks. Except for one patient who experienced grade 3 transient thrombocytopenia no major events of hematological or systemic toxicity were observed. Response rate (27%, 95% C.I., 10 to 44%), median duration of response (9 months, range 6-15), and survival (9.5 months, range 2-44+) were comparable to those achieved with conventional cisplatin-containing regimens. Our ICE combination, as compared to standard or high dose schedules appears effective, safe, well tolerated, and devoid of severe hematological toxicity.

Three conventional-drug combination (ifosfamide, carboplatin, etoposide--ICE regimen) in advanced non-small cell lung cancer (NSCLC).

Fifty consecutive patients with stage IIIB-IV non-small cell lung cancer (NSCLC) received the ICE regimen at intermediate doses (ifosfamide 1 g/m2, carboplatin 120 mg/m2, etoposide 80 mg/m2, day 1 to 3, q.4 weeks, for a maximum of 6 cycles). Overall 2 complete response (CR) and 10 partial response (PR) (overall response, OR: 24%, 95% C.I. 14-37%) were observed. An additional 7 patients had stable disease (SD) lasting more than 6 months, therefore a clinical benefit (CR+PR+SD >6 mos) was achieved in 19 patients (38%). Median time-to-progression (TTP) was 7 months and median overall survival (OS) was 11 months; 1- and 2-year survival rates were 36% and 10%. The ICE regimen was well tolerated and devoid of any cardiac, hepatic or neurologic toxicity. Moderate nausea and vomiting were easily manageable, grade 2 alopecia was universal, while hematological toxicity was mild (grade 2 leuko- and thrombocytopenia). Due to its efficacy and safety profile, this 3-drug regimen can be considered for routine community use.

Acute effects of glibenclamide on reactive hyperaemia in the lower limbs in humans.

Three episodes of 1 min ischemia in the lower limbs in humans reduced the metabolic debt repayment (expressed as AUC of reactive hyperaemia) following more prolonged ischemia (666.6+/-86.6 vs 500.0+/-33.5 ml/100 ml). The administration of the ATP-dependent K(+) channel blocker glibenclamide was associated with a significant reduction in the AUC of reactive hyperaemia (666.6+/-86.6 vs 563.1+/-76.6 ml/100 ml), and with the removal of the protective effect produced by 3 episodes of 1 min ischemia (563.1+/-76.6 vs 551.8+/-71.3 ml/100 ml). Plasma level of glibenclamide reached the peak value of 1.295+/-0.15 micromol/l 2 h after drug administration, ranging around the 1 micromol/l concentration in the following 3 hours. Our findings produce indirect evidence that, similarly to the ischemic preconditioning of the heart, the protective effects towards ischemia of brief repeated episodes of sub-maximal occlusion in the peripheral circulation of the lower limbs in humans are mediated by ATP-dependent K(+) channels.