Pharmacoeconomic management of patient with severe asthma in the Emergency Department: retrospective multicentric and cost of illness study.

OBJECTIVE: The aim of the study was to develop a cost-of-illness model that would investigate the costs associated with the management of patients suffering from asthma and severe asthma in the context of acute episodes managed in the emergency room. PATIENTS AND METHODS: A total of 795 records were collected between adults and paediatric patients. The data collection form reported an identification code for each patient included, gender, age, main discharge diagnosis, medical examinations carried out in the emergency room, the hospitalizations, and, if required by the patient condition, an outpatient visit performed by a pneumologist after the acute event that led the patient to the emergency room. In addition, the data collection form included information related to the pharmacological therapy taken by the patient. RESULTS: Among adult patients who had an admission with an asthma diagnosis, the average cost for the management of an adult patient in a green code in the emergency room is €330.39. As for the yellow code and the red code, the cost rises respectively to €444.04 and €808.25. The paediatric population has a slightly higher cost. As for the green code, the average cost stands at €355.87, for the yellow code €562.34 and €1,041.96 for the red code. CONCLUSIONS: Asthma and severe asthma impose a high burden on patients and society due to its chronicity, losses of productivity, and an increase in use of healthcare resources. We carried out the present observational retrospective analysis on asthma and severe asthma patients with the aim of assessing the economic impact from the Italian NHS perspective focusing also on the prescribed pharmacological therapies in the target conditions.

Effect of novel nociceptin/orphanin FQ-NOP receptor ligands on ethanol drinking in alcohol-preferring msP rats.

Activation of the NOP receptor by the endogenous ligand nociceptin/orphanin FQ (N/OFQ) reduces alcohol consumption in genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The present study evaluated the effect of three newly synthesized peptidergic and one brain-penetrating heterocyclic NOP receptor agonists on alcohol drinking in the two bottle choice paradigm. MsP rats were intracerebroventricularly (ICV) injected with the NOP receptor agonists OS-462 (0.5 and 1.0 microg), UFP-102 (0.25 and 1.0 microg) or UFP-112 (0.01 and 0.05 microg), or with Ro 64-6198 (0.3 and 1.0 mg/kg) given intraperitoneally (i.p.) and tested for 10% alcohol consumption. Results showed decreased alcohol consumption after treatment with all three peptidergic NOP receptor agonists (OS-462, UFP-102 and UFP-112). OS-462 (at the 1.0 microg dose) and UFP-102 (at the 0.25 microg dose) induced a significant increase in food intake as well. Surprisingly, Ro 64-6198 was ineffective at the 0.3 mg/kg dose, whereas it increased ethanol and food consumption at the 1.0 mg/kg dose. Pre-treatment with the selective mu-receptor antagonist naloxone (0.5 mg/kg, i.p.) reduced these effects of 1.0 mg/kg of Ro 64-6198. These findings confirm that activation of brain NOP receptors reduces alcohol drinking in msP rats and demonstrate that OS-462, UFP-102 and UFP-112 act as potent NOP receptor agonists. On the other hand, Ro 64-6198 increased alcohol drinking, an effect probably induced by a residual agonist activity of this compound at mu-opioid receptors. Overall, the results indicate that OS-462, UFP-102 and UFP-112 may represent valuable pharmacological tools to investigate the functional role of the brain N/OFQ system.

Pregnancy in immigrant women.

OBJECTIVE: We wanted to study how foreign women face pregnancy and childbirth in a society quite different from their own. METHODS: In 2004 we studied 328 pregnant women at the Department of Gynaecology at the "General Hospital Umberto I" in Rome. Information on patients' personal lives and experiences was collected. RESULTS: Women were classified into six (6) groups based on nationality, race, religion and culture. CONCLUSIONS: Arabian women had the most natural childbirths. African women had a longer duration of gestation. Women from Eastern Europe underwent frequent tests and examinations, but had the highest chance of having preterm births. Chinese women did not usually undergo many examinations and were able to tolerate pain during childbirth quite well.

Cytokinetic effects of interferon in colorectal cancer tumors: implications in the design of the interferon/5-fluorouracil combinations.

Interferon (IFN) has been shown to enhance the cytotoxic effects of 5-fluorouracil (5FUra) in colorectal cancer, and clinical trials with this combination resulted in higher response rate with respect to 5FUra alone. IFN is generally administered s.c. three times a week. This prolonged exposure could determine a block of tumor cells in the G0-G1 phase of the cell cycle, thus rendering tumor cells insensitive to 5FUra, an S-phase specific agent. In order to verify the presence of this block, 21 operable colorectal cancer patients were treated with IFN-alpha 2b at the dose of 3 megaunits every other day in the week before operation, while another 22 represented the control group. Samples of tumor tissue were taken at endoscopy and operation. [3H]Thymidine labeling index and flow cytometry were used to assess the S-phase fraction. In IFN treated patients, we found a significant statistical difference between the mean percentage of S-phase fractions evaluated either by labeling index (P = 0.00001) or by flow cytometry (P < 0.001). On the contrary, this difference was not present in the control group: labeling index, P = 0.06; flow cytometry, P = 0.08. Furthermore a significant increase in the G0-G1 phase of the cell cycle was found after IFN administration (P < 0.001) but not in the control group. Our results suggest that IFN reduces the S-phase fraction in colorectal cancer tumors. This action should be considered in the design of the 5FUra/IFN combination because it could decrease 5FUra activity, leading to a loss or a decrease in the advantage of 5FUra modulation by IFN.

Octreotide versus loperamide in the treatment of fluorouracil-induced diarrhea: a randomized trial.

PURPOSE: Diarrhea is a prominent feature of fluorouracil (5FU) gastrointestinal toxicity, especially when 5FU is combined with leucovorin (LV) or interferon (IFN). No treatment for this condition has been well defined, although drugs, such as diphenoxylate or loperamide, generally are used. The efficacy of octreotide in the treatment of 5FU-induced diarrhea recently has been reported. We performed a randomized trial that compared octreotide with loperamide, the drug most commonly used for therapy for this disorder. PATIENTS AND METHODS: Forty-one patients with grade 2 (four to six stools per day) or grade 3 (seven to nine stools per day; National Cancer Institute toxicity criteria) diarrhea after chemotherapy with a 5FU-containing regimen for colorectal cancer in 28 cases, gastric cancer in six cases, pancreatic cancer in five cases, and breast cancer in two cases, were entered onto the study. Twenty-one patients received octreotide at a dosage of 0.1 mg subcutaneously twice per day for 3 days, and 20 patients received loperamide 4 mg orally initially and then 2 mg every 6 hours for 3 days. The two arms were comparable for age, sex, and primary tumor. Patients were evaluated for response each treatment day; all patients were assessable. RESULTS: Diarrhea resolved in 19 patients in the octreotide arm (one within the first day; four within the second day; and 14 within the third day) versus only three (all after the third day of therapy) in the loperamide arm (P < .005). Median frequency of stools in the 3 days of therapy was four, three, and zero in the octreotide arm and five, five, and five in the loperamide arm. No side effects were observed in both arms. Ten patients on the loperamide arm and only one on the octreotide arm required hospitalization for parenteral replenishment of fluids and electrolytes. CONCLUSION: Octreotide seems to be more effective than loperamide in control of diarrhea and elimination of the need for replenishment of fluids and electrolytes.

Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo.

PURPOSE: To evaluate the effect of exogenous recombinant human erythropoietin (rHuEPO) on the increase of hemoglobin levels and on the transfusion requirements in patients with cisplatin (CDDP)-induced anemia, we performed a double-blind randomized trial with placebo. PATIENTS AND METHODS: One hundred patients with CDDP-associated anemia (hemoglobin level < 90 g/L) were randomized to receive either placebo (saline solution) or rHuEPO (100 U/kg body weight subcutaneously) three times per week. The end points of this study were the increase in hemoglobin levels to greater than 100 g/L after 3, 6, and 9 weeks and the effect on transfusion requirements. RESULTS: Ninety-nine of 100 patients were assessable for response and toxicity. In the rHuEPO arm, mean hemoglobin levels were statistically significantly increased after the third, sixth, and ninth weeks of therapy (101.1 +/- 9.0, 102.4 +/- 6.6, and 105.1 +/- 9.4 g/L, respectively) compared with the mean baseline value (86.3 +/- 6.2 g/L). In the placebo arm, there were no increases in mean hemoglobin levels at the third, sixth, and ninth weeks (81.0 +/- 5.2, 81.3 +/- 9.2, and 81.2 +/- 11 g/L, respectively) compared with the mean baseline value (87.3 +/- 5.2 g/L). Furthermore only 20% of patients required blood transfusions in the rHuEPO arm versus 56% of patients in the placebo arm (P = .01), with a mean units of blood transfused per patient of 0.30 in the rHuEPO arm and 1.8 in the placebo arm (P = .01). Treatment was well tolerated, with no significant side effects. CONCLUSION: CDDP-induced anemia is corrected by rHuEPO, which results in reduced blood transfusion requirements.

Aspirin modulates LPS-induced nitric oxide release in rat glial cells.

Nitric oxide and prostaglandins are among the numerous substances released by activated glial cells. The aim of this study was to evaluate the effect of high-level aspirin on iNOS expression in cultured rat glial cells treated with lipopolysaccharide (LPS) as pathological stimulator. Using Western Blotting, we verified that aspirin enhanced LPS-induced iNOS expression and the presence of 15-deoxy-Delta(12,14)-prostaglandin (15d-PGJ2) suppressed this aspirin effect. However, the exposure of LPS-treated glial cells to aspirin resulted in a decrease of NO production. These results suggest that aspirin interferes with the cross-talk of prostaglandins and NO, blocking the endogenous negative control exerted by COX products on iNOS expression. On the other side, aspirin seems to act directly on iNOS reducing its activity, even if it does not completely block NO release by LPS-stimulated glial cells. Then aspirin could maintain homeostatic functions of NO, while it prevents toxic effects, corresponding to high NO concentrations.

Control of chemotherapy-induced diarrhoea with octreotide in patients receiving 5-fluorouracil.

Chemotherapy treatment with combination of 5-fluorouracil and leucovorin or interferon alpha determined an incidence of severe diarrhoea of 10 and 20%, respectively. Up to date no treatment for this condition has been defined. 21 patients affected by advanced colorectal cancer and 6 patients affected by advanced pancreatic cancer received octreotide as treatment for severe diarrhoea following chemotherapy with 5-fluorouracil/leucovorin (Machover's regimen) or 5-fluorouracil/interferon (Wadler's regimen) combination. Octreotide was administered by subcutaneous injection of 50 micrograms twice daily on the first day and 100 micrograms twice daily on the second and third day. 26 patients had total cessation of diarrhoea: 4 patients within the first day, 6 within the second day and 16 within the third day. 1 patient had no change and after the last administration of octreotide he was treated with loperamide and intravenous hydration. Side effects have been mild. In summary octreotide seems to be an effective agent in the management of chemotherapy related diarrhoea.

Intensive weekly chemotherapy for advanced gastric-cancer using 5-Fluorouracil, Cisplatin, epi-Doxorubicin, 6s-leucovorin and granulocyte-colony-stimulating factor.

Thirty-four advanced gastric cancer patients received, every week for nine weeks, 5-fluorouracil 500 mg/m2 iv; epi-doxorubicin 35 Mg/M2 iv; cisplatin 40 Mg/M2 iv; 6S-leucovorin 250 mg/M2 in 4 hour infusion. Granulocyte-colony stimulating factor, at the dose of 5 mug/kg, was administered daily from the day after to the day before each chemotherapy administration. 5 patients achieved a complete response and 20 a partial response, resulting in an overall response rate of 72% (95% confidence interval, 59% to 88%). Median survival time was 12 months for all the patients and 13 months for responding patients. Toxicity was mild. In conclusion, this regimen seems to be promising and suitable for further studies in gastric cancer.

Etoposide, leucovorin, 5-fluorouracil and interferon alpha-2b in elderly gastric cancer patients: a pilot study.

A total of 23 advanced gastric cancer patients older than 65 years received 500 mg/m2 5-fluorouracil i.v. on days 2-4, 120 mg/m2 vepesid i.v. on days 2-4, 150 mg/m2 6S-leucovorin on days 2-4, and 5 MU/m2 interferon alpha-2b on days 1-5, with cycles being repeated every 3 weeks. Toxicity was severe at an interferon (IFN) dose of 5 MU/m2; only one patient tolerated this dose. In 18 patients an IFN dose of 3 MU/m2 and in 3 other patients a dose of 4 MU/m2 could be given without producing toxicity. At an IFN dose of 5 MU/m2 the most common toxicities encountered were stomatitis (grade 4 in 1 patient and grade 3 in 12 patients), leukopenia (grade 4 in 1 patient and grade 3 in 5 patients), and thrombocytopenia (grade 3 in 3 patients). Two patients achieved a complete response and eight showed a partial response, resulting in an overall response rate of 45% [95% confidence interval (CI), 25%-64%]. The median survival was 7 months for all patients and 9 months for responding patients. In conclusion, without substantially increasing the toxicity, IFN can be added to the etoposide/leucovorin/5-fluorouracil combination, at a dose of 3 MU/m2. To verify the possible enhancement by IFN of the activity of this combination, a randomized trial is under way.

Multimodal biochemical modulation of 5-fluorouracil by leucovorin, methotrexate, and interferon alpha in patients with advanced colorectal cancer.

A total of 26 patients with advanced colorectal cancer received 60 mg/m2 methotrexate i.v. on days 1-4; 400 mg/m2 5-fluorouracil i.v. on days 2, 3, 5, and 6; and 100 mg/m2 6S-leucovorin i.v. on days 2, 3, 5, and 6. Interferon-alpha 2b at a dose of 3 million U was given i.m. daily for the 6 days of chemotherapy. Courses were repeated every 3 weeks. There were four partial responses for a response rate of 15% (95% confidence interval 2-28%): In all, 14 patients expressed grade 3 toxicity; 9 patients had diarrhea, 3 had stomatitis, and 2 developed leukopenia. In conclusion, multimodal biochemical modulation of 5-fluorouracil, at least on this schedule, does not seem to be effective, as it results in severe toxicity.

Carboplatin associated anemia treated with subcutaneous erythropoietin - a pilot-study.

In nineteen patients with carboplatin-induced anemia (hemoglobin less than 90 g/l), recombinant human erythropoietin was administered subcutaneously three times a week on an outpatient basis. The initial dose was 50 Units/kg of body weight. If response was not achieved within 3 weeks, dose was increased to 75 Units/kg. Using the same criteria further escalations to 100 and 150 Units/kg were performed. If there was no response erythropoietin was terminated. Two patients obtained an increase of hemoglobin levels greater than 100 g/l, which was considered as a clinical response in this study, with a dose of 75 U/kg; eleven patients needed an erythropoietin dose of 100 U/kg and three a dose of 150 U/kg. The other three patients required hemotransfusions and were considered non responders. Hemoglobin increases occurred despite continuation of carboplatin chemotherapy. In conclusion, subcutaneous eryhtropoietin is effective and safe in the treatment of carboplatin-induced anemia.

Oral escalating dose of cyclosporine-a combined with 4-epidoxorubicin in advanced colorectal-cancer - a phase-I study.

Multidrug resistance, a major factor in the resistance to drugs, can be reversed by cyclosporin A. It is generally given by intravenous route. The aim of the present study was to assess the possibility of achieving useful plasma levels, giving cyclosporin A orally in advanced colorectal cancer patients treated with 4-epidoxorubicin. Cyclosporin A was given orally twice a day, for four days. The starting study dose was 5 mg/kg. Dose in cohorts of 3 patients was escalated to 10, 15, 20, 30, 40 mg/kg if the previous dose was not able to determine the target blood level (2,000 ng/ml). Cyclosporin A blood levels were analyzed by a specific fluorescence polarization immunoassay method (TDx; Abbot Laboratoires, North Chigaco, IL). 4-epidoxorubicin was given at a fixed dose of 75 mg/m(2), every 3 weeks. None of the dose levels of cyclosporin A given orally produced the target blood level. Only two patients, receiving cyclosporin at a dose of 30 mg/kg, and two after a CsA dose of 40 mg/kg, presented blood levels higher than 1,000 ng/ml, but however, lower than 1,500 ng/ml. In conclusion, the oral route of administration of cyclosporin does not seem recommendable in order to reverse multidrug resistance because it is not able to produce sufficient plasma levels.

The clinical impact of FEM regimen (5-fluorouracil, 4-epidoxorubicin and mitomycin-C) in advanced gastric cancer patients.

The activity of FEM regimen in metastatic gastric cancer patients was assessed in seventy-seven patients receiving, as palliative treatment, 5FU 600 mg/m2 i.v. on days 1, 8, 29, 36; epiADR 70 mg/m2 i.v. on days 1, 29; MIT-C 10 mg/m2 i.v. on days 1, 29. Cycles were repeated every 58 days. One patient achieved a complete response and 12 a partial response, resulting in an overall response rate of 16% (95% CI: 8% to 24%). Median remission duration was 6 months. Median survival time for all patients was 8 months. Side-effects were mild and principally in the form of leukopenia (three episodes grade III). Our results support the recent findings about the lack of effectiveness of this regimen. Although it is a safe and well tolerable chemotherapeutic combination, FEM regimen should not be recommended as routinary treatment for gastric cancer patients who are not eligible for clinical trials.

A new cisplatin/gemcitabine schedule in locally advanced (IIIB) and metastatic (IV) non-small cell lung cancer: relationship between dose-intensity and efficacy. A phase II study.

BACKGROUND: Cisplatin/gemcitabine are one of the "standard" chemotherapy schedules in locally advanced and metastatic NSCLC cancer. A number of trials documented that omission of gemcitabine on day 15 and reduction of cisplatin up to 70 mg/mq are equivalent in term of response rates to "classic" administrations on days 1, 8 and 15 with cisplatin 100 mg/mq. The aim of this study was to confirm this evidence and to demonstrate that a further reduction of gemcitabine dose-intensity may be performed with the same efficacy on response. PATIENTS AND METHODS: Fifty untreated patients with locally advanced and metastatic NSCLC entered the study: 24 stage IIIB and 26 stage IV. The median age was 65 years (range 32-76); 44 males and 6 females Genicitabine was administered 1000 mg/mq weekly on days 1 and 8 followed by a 2-week rest and cisplatin 80 mg/mq on day 2 of each 28-day-cycle. RESULTS: Forty-five patients were evaluable for response and all for toxicity. The overall response rates were 35.5% with 16 partial responses (95% Confidence Interval: 32%-61%). Most of the objective responses were seen in IIIB patients (56% of the stage IIIB and 44% of the stage IV patients responded). According to the intent-to-treat-principle, the response rates were 32% (16 out of 50 patients). The median dose-intensity of gemcitabine and cisplatin was respectively 477.6 mg/mq/week (481.4 for responders) and 19.5 mg/mq/week (19.9 mg/mq for responders). The median response duration was 5 months (range 1-18) and the median time to progression was 5 months (1-21); median survival was 9 months (range 2-31). The main toxicity was haematological: thrombocytopenia grade IV in 5 patients (10%) and grade III in 11 patients (22%); neutropenia grade III-IV in 4 patients (8%); grade III anemia in 3 (6%). Asthenia was the most significant non-haematological toxicity and was observed in 19 patients (38%). CONCLUSION: This trial confirmed the efficacy of a schedule with 2 administrations of gemcitabine (on days 1, 8) and a cisplatin dose on day 2 lower than 100 mg/mq. Moreover, the same efficacy was obtained with a median-dose intensity of cisplatin and gemcitabine lower than planned in a 21-day-schedule. For safety and low toxicity, we think that this schedule provides another chance to treat patients with non-small cell lung cancer, especially the elderly or patients with coexistent medical illnesses.

Tumor markers in the diagnosis of malignant serous effusions.

To assess the possibility of increasing the detection rates of cytological examination in malignant effusions by the selection of specific tumor markers for a given type of tumor, we measured CEA, CA 19.9, CA 15.3, MCA, PSA, and AFP in malignant effusions from 89 patients with the following primary malignancies: colon, stomach, breast, liver, prostate, lung, and kidney. Cytological examination was positive in only 35 of 89 patients (40%), while the tumor markers were positive in 72 of 89 cases (80%). However, apart from small cell lung and kidney cancers, where the lack of a specific tumor marker resulted in no advantage, in the other types of tumors, the specific marker for each tumor identified correctly malignant effusions in 72 of 74 cases (97%). In fact, CEA was positive in 11 of 11 effusions induced by colorectal cancer; CA 19.9 in 28 of 30 gastric cancer effusions, while MCA and CA 15.3 were positive in breast cancer effusions (16/22 and 20/22). Finally, elevated AFP and PSA indicated hepatocellular and prostate cancer, respectively. In conclusion, in cancer patients with elevated effusion levels of specific tumor markers, the effusions could be considered of a malignant nature even without cytologically demonstrable tumor cells.

Breast cancer developing after therapy for Hodgkin's disease.

Two patients developed breast cancer 14 and 8 years after treatment of Hodgkin's disease. Both had received mediastinal irradiation and MOPP chemotherapy. Because of the increased risk of breast cancer in women treated for Hodgkin's disease, as reported in the literature, we suggest the early initiation of periodic screening for breast cancer, to detect possible neoplasms at a more treatable stage.

5-Fluorouracil dose intensity increase in 5-fluorouracil and leucovorin combination: results of a phase II study.

It was our intention to verify if in the combination of 5-fluorouracil and leucovorin, the fluoropyrimidine dose intensity is an important determinant of response as noted by Hryniuk when 5-fluorouracil was given alone. By employing the Machover regimen but with cycles repeated every three weeks, a 5-fluorouracil projected dose intensity of 616 mg/m2/wk was obtained. It approximates the maximum tolerated dose for this drug when used alone by i.v. bolus. 50 patients entered this study and 48 were evaluable for response and toxicity. The overall response rate was 29% (five complete responses and nine partial responses). The dose limiting toxicity was gastrointestinal rather than myelosuppression. 5-fluorouracil dose reduction was needed in seven patients. The mean delivered dose intensity of 5-fluorouracil was 610 mg/m2/wk (582 mg/m2/wk in patients in whom 5-fluorouracil was reduced for toxicity and 616 mg/m2/wk in the others). Our results do not seem to show any advantage in the maximization of 5-fluorouracil dose intensity. Furthermore, in an analysis of data from the literature we did not find any difference in response rate in relation to dose intensity in the 5-fluorouracil/leucovorin combination.

Salvage chemotherapy in colorectal cancer patients with good performance status and young age after failure of 5-fluorouracil/leucovorin combination.

Forty-one patients with metastatic colorectal cancer were treated every four weeks with methotrexate 25 mg/m2 i.v. days 1, 8, 15; vincristine 1 mg/m2 i.v. day 1; lomustine 100 mg/m2 p.o. day 1. Inclusion criteria were: failure of previous 5-fluorouracil/leucovorin treatment; performance status (ECOG) 0-2; age less than 60 years; presence of symptoms; absence of concomitant diseases. Metastatic sites were: liver 30, lung 4, abdominal/pelvic mass 7. Three patients achieved partial responses (2 liver, 1 lung metastases); 4 showed stable disease and 34 progressed on therapy. The median survival of patients with partial response, stable disease and progression was comparable (24, 21, 22 weeks respectively). The most common toxicity was hematologic (thrombocytopenia and leukopenia). Other side effects included nausea and vomiting, stomatitis and diarrhea. Symptoms were not affected by treatment. We conclude that salvage chemotherapy is not recommended in colorectal cancer after 5-fluorouracil/leucovorin treatment even in patients with generally considered favorable characteristics for response to chemotherapy.

Treatment of elderly advanced gastric cancer patients with 5-fluorouracil and leucovorin combination.

In September 1987 a phase II study was begun to verify if elderly symptomatic patients affected by advanced gastric cancer could benefit from a combination of 5-fluorouracil (5FU) and leucovorin (LV). We employed Machover's regimen: 5FU 370 mg/m2 i.v. infusion daily for 5 days; LV 200 mg/m2 i.v. bolus daily for 5 days; cycles were repeated every 3 weeks. 23 patients entered the study and 22 were evaluable for response and toxicity. We obtained only one partial response; 9 had stable disease and 12 progressed on therapy. The median duration of survival was 6 months. Symptoms were not affected by treatment. These data reflect the absence of significant improvement in the quality of life, which was further lessened by the presence of treatment side effects. Because of this we think that this regimen cannot be recommended for the treatment of elderly advanced gastric cancer patients.