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What is known and objective Mebendazole (MBZ) is a broad-spectrum antihelminthic agent of the benzimidazole type. Although MBZ has been reported to cause hepatic injury, case reports of severe hepatic injury are very rare. We report a case of severe hepatitis after administration of MBZ in a patient with Gilbert's syndrome affected by pinworms infestation. Case summary Differently from other cases of hepatitis due to MBZ reported in the scientific literature, our patient received standard doses of MBZ for a short period of time. After 18 days from the start of therapy, he developed hepatomegaly, and increases in hepatic enzymes and bilirubin. Hepatic enzymes returned to normal over the following 5 weeks. What is new and conclusion This is the first case report of important liver injury after administration of MBZ in a patient with Gilbert's syndrome. We suspected that a diminished hepatic glucuronidation of MBZ due to the reduced activity of the glucuronosyltransferase enzyme in our patient could have caused an increase in unconjugated toxic metabolites of MBZ and the consequent liver damage.

STAT5 is a transcription factor, a member of the STAT family of signaling proteins. STAT5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), in which this protein is found constitutively activated as a consequence of BCR-ABL expression. The neuroleptic drug pimozide was recently reported to act as an inhibitor of STAT5 phosphorylation and is capable of inducing apoptosis in CML cells in vitro. Our research group has synthesized simple derivatives of pimozide with cytotoxic activity and that are able to decrease the levels of phosphorylated STAT5. In this work we continued the search for novel STAT5 inhibitors, synthesizing compounds in which the benzoimidazolinone ring of pimozide is either maintained or modified, in order to obtain further structure–activity relationship information for this class of STAT5 inhibitors. Two compounds of the series showed potent cytotoxic activity against BCR-ABL-positive and pSTAT5-overexpressing K562 cells and were able to markedly decrease the levels of phosphorylated STAT5.

The JAK-STAT pathway is an important physiologic regulator of different cellular functions including proliferation, apoptosis, differentiation, and immunological responses. Out of six different STAT proteins, STAT5 plays its main role in hematopoiesis and constitutive STAT5 activation seems to be a key event in the pathogenesis of several hematological malignancies. This has led many researchers to develop compounds capable of inhibiting STAT5 activation or interfering with its functions. Several anti-STAT5 molecules have shown potent STAT5 inhibitory activity in vitro. However, compared to the large amount of clinical studies with JAK inhibitors that are currently widely used in the clinics to treat myeloproliferative disorders, the clinical trials with STAT5 inhibitors are very limited. At present, a few STAT5 inhibitors are in phase I or II clinical trials for the treatment of leukemias and graft vs host disease. These studies seem to indicate that such compounds could be well tolerated and useful in reducing the occurrence of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Of interest, STAT5 seems to play an important role in the regulation of hematopoietic stem cell self-renewal suggesting that combination therapies including STAT5 inhibitors can erode the cancer stem cell pool and possibly open the way for the complete cancer eradication. In this review, we discuss the implication of STAT5 in hematological malignancies and the results obtained with the novel STAT5 inhibitors.

Resistance to imatinib mesylate is an emergent problem in the treatment of Bcr-Abl expressing myelogenous leukemias and additional therapeutic strategies are required. We observed that galangin, a non-toxic, naturally occurring flavonoid was effective as anti-proliferative, and apoptotic agent in Bcr-Abl expressing K562 and KCL22 cells and in imatinib mesylate resistant K562-R and KCL22-R cells. Galangin induced an arrest of cells in G0–G1phase of cell cycle and a decrease in pRb, cdk4, cdk1, cycline B levels; moreover, it was able to induce a monocytic differentiation of leukemic Bcr-Abl+ cells. Of note, galangin caused a decrease in Bcl-2 levels and markedly increased the apoptotic activity of imatinib both in sensitive or imatinib-resistant Bcr-Abl+ cell lines. In contrast, flavonoids unable to modify the Bcl-2 intracellular levels, such as fisetin and chrysin, did not increase the apoptotic effect of imatinib. These data suggest that galangin is an interesting candidate for a combination therapy in the treatment of imatinib-resistant leukemias.

Background Proton pump inhibitors (PPIs) are among the most misused drugs both at the community and hospital level. Recently, possible risks have been underscored, suggesting the importance of limiting PPI use to proven indications. Objective To survey the appropriateness of PPI use in a University hospital in Italy. Setting Azienda Ospedaliera Universitaria Policlinico ‘P. Giaccone’, in Palermo, Italy. Method A one day-observational study, reviewing patients’ medical records to identify treatments with PPIs and the indications for their use. After discharge, a subgroup of the cohort was followed up to assess the continuation of therapy at home. Appropriateness was evaluated according to the indications stated in the official product information sheet and supported by the AIFA notes. Main outcome measure Prevalence and appropriateness of PPI use in the hospital and after discharge. Results In the index day 62.9 % of 343 evaluable patients received a PPI. In only 29.1 % of these, the treatment could be considered appropriate. The most frequent reasons for inappropriate treatment were stress ulcer prophylaxis in low risk patients and unwarranted gastro-protection in drug treated patients. 30.9 % of patients received PPIs for uncertain indications: of these, 25.7 % were “critical” patients admitted in non-ICU wards. Furthermore, as much as 88.2 % of anticancer drug treated patients received PPIs as gastroprotective agents. At discharge 48.6 % of patients received a prescription to continue PPI therapy at home and 75.9 % of the 83 followed up patients were found to be still taking these drugs after on average 3 months from discharge. Conclusion This study confirms a high proportion of inappropriate PPI therapy into the hospital that translates in a prolonged unnecessary administration in the community setting. Further studies are needed to assess the cost-effectiveness of PPI therapy in subgroups of patients at moderate risk for gastric complications to optimize current guidelines.

Failure to perform the Fas-related apoptosis pathway can account for tumor resistance both to chemotherapeutic agents and to immunological effectors. We studied the role of NK-kappaB in Fas-resistance, employing the Fas-sensitive human T-lymphoma HuT78 cell line and its Fas-resistant variants HuT78B1 and HuT78G9. All these cell lines expressed high levels of constitutively activated NF-kappaB. Pretreatment of cells with NF-kappaB inhibitors (PDTC, MG132, or SN50) strongly enhanced CH11-induced apoptosis in HuT78 and Hut78G9 cells, while only MG132 showed a similar potentiating effect in HuT78B1. The described synergism was significantly inhibited by pretreatment with the anti-Fas-blocking antibody ZB4 or with the pancapsase inhibitor Z-VAD-FMK, but not by capsase-8 or -9 inhibitors. Overall, these data suggest that NF-kappaB inhibition may restore the Fas-pathway in Fas-resistant NF-kappaB-overexpressing tumors.

STATs are transcription factors acting as intracellular signaling after stimulation with cytokines, growth factors and hormones. STAT5 is also constitutively active in many forms of cancers, including chronic myelogenous leukemia, acute lymphoblastic leukemia and Hodgkin's lymphoma. Recently, literature reported that the neuroleptic drug pimozide inhibits STAT5 phosphorylation inducing apoptosis in CML cells. We undertook an investigation from pimozide structure, obtaining simple derivatives with cytotoxic and STAT5-inhibitory activity, two of them markedly more potent than pimozide.

The identification of novel compounds modulating the expression/activity of molecular targets downstream to BCR-ABL could be a new approach in the treatment of chronic myeloid leukemias (CMLs) resistant to imatinib or other BCR-ABL-targeted molecules. Recently, we synthesized a new class of substituted 2-(3,4,5-trimethoxybenzoyl)-2-N,N-dimethylamino-benzo[b]furans, and among these 3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone (TR120) showed marked cytotoxic activity in BCR-ABL-expressing cells. Interestingly, TR120 was more potent than imatinib in cell growth inhibition and apoptosis induction in both BCR-ABL-expressing K562 and KCL22 cells. Moreover, it showed antitumor activity in imatinib-resistant K562-R and KCL22-R cells at concentrations similar to those active in the respective sensitive cells. Further, TR120 induced a marked decrease in signal transducer and activator of transcription 5 (STAT5) expression in K562 cells. Consistent with this effect, it determined a block of cells in the G0-G1 phase of the cell cycle, a decrease in the level of cyclin D1, and a reduction in Bcl-xL expression; however, it did not cause modifications in the Bcl-2 level. Of interest, TR120 had synergistic effects when used in combination with imatinib in both sensitive and resistant cells. Considering that STAT5 is a BCR-ABL molecular target that plays a key role in the pathogenesis of CML as well as in BCR-ABL-mediated resistance to apoptosis, TR120 could potentially be a useful novel agent in the treatment of imatinib-resistant CML.

Treatment of advanced head and neck cancer is still a matter of controversy. Although current chemotherapy regimens are able to induce high response rates, they have not shown improved survival. We employed a combination of cisplatin (CDDP), 5-fluorouracil (5FU) and 1-folinic acid (1-FA) in a 6-hour infusion schedule easy to administer on an outpatient basis. 49 patients have been included to date. The treatment plan consists of 5-FU (375 mg/m(2)) plus 1-FA (100 mg/m(2)) in a 4-hour i.v. infusion followed by a 2-hour i.v. administration of CDDP (20 mg/m(2)). This therapy was repeated for five consecutive days and recycled every 3-4 weeks. Out of 46 evaluable patients there were 6 complete responses (CR) and 23 partial responses (PR) for an overall response rate of 63%. Overall survival was 10.2 months (mean). Untreated patients had a higher probability of response as well as patients with naso-oropharyngeal primary tumor. Toxicity was generally mild with leukopenia, anemia and vomiting being the most frequent side effects. In conclusion, this combination appears well tolerated and active in the palliation of advanced head and neck cancer. However we think that increasing dose intensity of standard regimens and experimental new therapeutic approaches are needed to improve the clinical outcome of this disease.

We enrolled 11 consecutive pre-treated resistant advanced cancer patients to receive hydroxyurea (HU) (as modulator of MDR) 10 mg/kg/day (d) p.o. d 1-14 in association with DXR (d 15) alone or in combination with VDS (d 15) or VP16 (d 15-17) in presence, respectively, of soft tissue sarcoma, breast carcinoma, lung and gastric carcinoma. We obtained a stabilization of disease (NC) in 62.5% of patients, with a mean duration of 6 months. The mean survival was 12.2+ months for NC and 6 months for progressive disease (PD). No severe or unexpected adverse events were reported over 34 cycles administered; the most frequently recorded side effects were haematological and gastrointestinal toxicity. It seems that at the dosage we used, HU is poorly active in overcoming MDR; further studies with larger number of patients and different dosage are needed.

Twenty consecutive patients with advanced breast cancer were treated with a combination of cyclophosphamide 600 mg/m2 i.v. on day 1, epidoxorubicin 75 mg/m2 on day 1, and 5-fluorouracil 375 mg/m2 i.v. with folinic acid 200 mg/m2 i.v. on days 1----3. The overall response rate was 60%, with 10% of patients showing a complete response with a mean duration of 11.1 + months, and 50% of patients a partial response of 7.4 + months. A stabilization of 5.2 + months was obtained in 20% of cases, while 20% of patients progressed. The most frequently observed toxicity was leukopenia, while expected mucosal toxicities were rather mild.

IAPs (inhibitors of apoptosis proteins) might have a major role in the apoptotic resistance that marks many cancers. The studies on IAPs in human HCC have focused on survivin or XIAP, indicating that their new or increased expression in this tumor is associated with a more unfavorable prognosis. The present results corroborate these findings, emphasizing the role that the coordinated expression of different IAPs and alternative splice variants might play in the adverse biology of hepatocellular carcinoma.

Background: The effects of the A3 adenosine receptor (A3AR) agonist IB-MECA were examined in HL-60 leukemia and in its multidrug-resistant variant HL-60R cells. Methods: Cytotoxicity was evaluated by MTS assays and apoptosis by flow cytometry analyses of DNA fragmentation and phosphatidylserine exposure. The mRNAs of A3AR and inhibitor of apoptosis proteins (IAPs) were determined by RT-PCR. Results: A3AR expression was similar in HL-60 and HL-60R cells. At ≧100 µM, IB-MECA exhibited strong cytotoxic and apoptotic effects in HL-60, but not in HL-60R cells. This activity was not modified by the A3AR antagonist VUF5574, the P-glycoprotein inhibitor verapamil, the adenosine uptake inhibitor NBTI or the anti-Fas antibody ZB4. HL-60R cells showed higher levels of different IAPs than HL-60 cells. IB-MECA 100 µM downregulated HIAP1, NAIP and survivin mRNAs in HL-60, but not in HL-60R cells. Conclusions: The antitumor effects of IB-MECA are not mediated by A3AR in HL-60 cells, where the proapoptotic mechanism of the compound may involve downregulation of IAPs. The resistance of HL-60R cells to IB-MECA may depend on their elevated levels of IAPs.

The role of chemotherapy in refractory metastatic breast cancer is still debated. We employed a schedule of cisplatin, mitomycin and vindesine in twenty-one anthracycline- or anthraquinone-pretreated breast cancer patients. The most relevant characteristics of our group were a good performance status (mean Karnofsky index 84) and a high percentage of bone disease (71%). Out of 20 evaluable patients, 4 (20%) achieved a partial response with a median duration of 3.7 months. Median survival was 12.5 months. Severe gastrointestinal toxicity was reported in 66% of patients and G3 alopecia was seen in 24%. Other side effects, including hematological, were negligible. On the basis of the low response rate and poor tolerability we do not reccommend this combination as salvage treatment in metastatic breast cancer. The use of cisplatin-based regimens in untreated patients waits further investigation.

The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been tested in a clinical open multicenter trial on 2044 patients suffering from recent stroke or transient ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days and orally at the dose of 400 mg tid during the following 5 months after the first phase. The evaluation of the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS), and the Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end of the 5 month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, reaching the "normality" score at the 3rd month assessment. The GDS score at the end of the trial corresponded to "no cognitive decline" or "forgetfulness" in 71% of the patients. Adverse events were complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability.