Evidence for the efficacy of disulfiram and copper combination in glioblastoma multiforme - A propos of a case.

Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates. One of the most promising drugs to repurpose for treating GBM is disulfiram (DSF). DSF is a relatively nontoxic drug used for more than sixty years in the treatment of chronic alcoholism with the ability to readily cross the blood-brain barrier. Repurposing DSF for use as an anticancer drug in general has recently become of interest because of its preclinically described anticancer effects against various human cancers. Interestingly, a number of these effects were shown to be copper (Cu)-dependent. The purpose of this paper was to review the existing literature surrounding preclinical and clinical data on the effects of DSF -alone or in combination with Cu- in GBM. In addition, we present the first case of a GBM patient safely treated with DSF/Cu combination along with standard therapy exhibiting remarkably increased progression-free (PFS) and overall survival (OS).

Risk factors for infection and predictors of mortality among patients with KPC-producing Klebsiella pneumoniae bloodstream infections in the intensive care unit.

BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) infections in intensive care units (ICUs) are associated with increased mortality. We aimed to determine risk factors for infection and predictors of 30-day mortality in ICU patients with KPC-Kp bloodstream infections (BSI). METHODS: During a 26-month period, patients (n = 273) who stayed more than 6 days in the ICU of the University Hospital of Patras, Greece, were divided into 2 groups, those who developed KPC-Kp BSI and those who did not. K. pneumoniae was identified by Vitek 2 technology. Antibiotic susceptibility testing was performed by agar disk diffusion method. Minimum inhibitory concentrations were determined by Etest. The presence of the blaKPC gene was confirmed by PCR. Molecular typing was performed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Epidemiological data were collected by patient chart review. RESULTS: Five patients had bacteraemia upon admission, while in 48 (17.6%) the BSI developed after 6 days of hospitalization. Risk factors for KPC-Kp BSI in the latter group were the administration of aminoglycosides, number of invasive catheters inserted after the third day, and tracheostomy. The 30-day mortality was 43.4% (23/53 patients). Multivariate analysis revealed that age, SAPS II score at onset of BSI, resistance to colistin, gentamicin, or tigecycline, and septic shock were independently associated with mortality. Treatment with at least 2 appropriate antibiotics was identified as a predictor of a good prognosis. CONCLUSIONS: Many risk factors are involved in KPC-Kp BSI among ICU patients. The high mortality in patients with KPC-KP BSI in the ICU requires the implementation of appropriate infection control measures.

Quantification of superoxide radical production in 4 vital organs of rats subjected to hemorrhagic shock.

OBJECTIVE: The aim of this study was to measure the production of superoxide radical (O2-), a direct indicator of oxidative stress, in 4 vital organs of rats subjected to hemorrhagic shock. For this purpose, and for the first time, a new quantitative assay for the ex vivo measurement of O2- via an established 1:1 molar relationship between O2- and 2-OH-ethidium was used. The production of lipid hydroperoxides (LOOHs), a standard method of evaluation of oxidative stress, was also used for reasons of comparison. METHODS: Sixteen male Wistar rats were divided into 2 groups: sham and hemorrhagic shock, targeting to a mean arterial pressure of 30 to 40 mm Hg for 60 minutes. Three hours after resuscitation, tissues were collected for measurement of LOOHs and O2- production. RESULTS: Hemorrhagic shock induced increased production of LOOHs in the gut, liver, and lungs (P<.001), whereas the production of O2- was also increased in the gut (P<.001), liver (P<.001), and, to a lesser extent, in the lungs (P<.05). The oxidative load of the kidneys, as estimated by both techniques, remained unaffected. CONCLUSION: The results of this new O2- assay were comparable with the results of the established LOOHs method, and this assay proved to be accurate and sensitive in the detection and quantification of O2- production in all organs tested. Thus, the proposed direct measurement of O2- in critically ill patients often facing in extremis situations could be used as a prognostic tool and as a method to evaluate therapeutic interventions in the setting of emergency medicine.

Clonidine pre-treatment prevents hemorrhagic shock-induced endotoxemia and oxidative stress in the gut, liver, and lungs of the rat.

OBJECTIVES: To study the effect of clonidine pre-treatment on hemorrhagic shock (H/S)-induced endotoxemia and oxidative stress (OS) in three vital organs of the rat. METHODS: The study protocol consisted of two arms: one for the measurement of organic hydroperoxide (LOOH) and superoxide radical (O(2)(-·)) production in the gut, liver, and lungs (n = 32 rats) and one for the measurement of endotoxin in portal and systemic circulation (n = 32 rats). Four animal groups (sham, clonidine, H/S, and clonidine-H/S group) were used in each arm. Three hours after H/S and concominant blood resuscitation, tissues were collected for LOOHs and O(2)(-·) measurement and blood samples were obtained for endotoxin determination. RESULTS: Clonidine pre-treatment prior to H/S resulted in a significant reduction of LOOHs and O(2)(-·) production in all vital organs (P < 0.05-0.001), while additionally, clonidine reduced H/S-induced endotoxemia in portal (P < 0.05) and systemic circulation as well (P < 0.01). DISCUSSION: Clonidine pre-treatment prevents endotoxemia and OS in the gut, liver, and lungs of rats subjected to severe H/S. The improved intestinal barrier function probably stems from the antioxidant effect of clonidine on the intestinal epithelium, whereas the reduced endotoxemia may contribute to a decreased OS observed in the liver and lungs.

CYP2E1 and risk of chemically mediated cancers.

IMPORTANCE OF THE FIELD: Among various human CYPs, CYP2E1 is of particular interest because of its involvement in the metabolic activation of many low molecular mass procarcinogens. CYP2E1 induction, which may be a consequence of genetic polymorphism or/and gene induction by xenobiotics, is the first step leading to the development of certain chemically-mediated cancers. The aim of this review is to outline the current knowledge on chemically-induced cancers through activation by CYP2E1, with emphasis on the association between polymorphisms of the CYP2E1 gene and incidence of different neoplasias. AREAS COVERED IN THIS REVIEW: Literature searches of MEDLINE (1966 to July 2009) for English articles in CYP2E1-induced carcinogenesis were conducted. WHAT THE READER WILL GAIN: CYP2E1 genetic polymorphisms leading to enhanced CYP2E1 gene transcription have been associated with increased risk of development of malignant tumours, through increased biotransformation of procarcinogens. Likewise, long-term intake of CYP2E1 inducers, such as ethanol, isoniazid, various solvents and chemicals, also increase the probability of developing malignancy, especially for carriers of certain CYP2E1 alleles. TAKE HOME MESSAGE: Genetic screening for CYP2E1 'carcinogenic' polymorphisms and CYP2E1 phenotype determination of susceptible subjects, as well as the development of effective CYP2E1 inhibitors, could be a future perspective towards prevention of CYP2E1-mediated cancers.

Patient and/or family controlled palliative sedation with midazolam for intractable symptom control: a case series.

INTRODUCTION: Our case series prospectively evaluate the concept of Patient/Family-Controlled Sedation with midazolam, as an alternative to sedation by continuous infusion in terminal cancer patients. CASES PRESENTATION: Our method was applied in 8 pts. Midazolam was administered in a Patient Control Analgesia mode. The infusion pump was activated "as-needed" by the pt or a caretaker. Sedation was rated as: 1) awake 2) arousable to voice 3) arousable to light pain or 4) unarousable. Family satisfaction was rated as: 1) good, 2) fair, 3) poor, or 4) unacceptable. Mean midazolam consumption was 12 - 40 mg/24 hours. We did not observe respiratory depression. Death occurred 1-6 days after sedation started. Family satisfaction was mainly good and median sedation was in the range 2 - 3. CONCLUSION: Patient/Family-Controlled Sedation with midazolam was effective in providing comfort, by allowing titration of sedation to each patient's needs.