A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3.

BACKGROUND: The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. We designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide-version 3-(CUSP9v3) to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3. METHODS: Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3-4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle. RESULTS: One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%. CONCLUSIONS: CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

[Arterial Hyper- and Hypotension associated with psychiatric medications: a risk assessment based on the summaries of product characteristics (SmPCs)]. / Arterielle Hyper- und Hypotonie assoziiert mit Psychopharmaka: eine Risikobewertung basierend auf den Fachinformationen.

Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure. Results According to the SmPCs, atomoxetine had the highest risk of arterial hypertension ("very frequent", > 10 %), and another 15 substances followed in the category "frequent" (> 1 %): duloxetine, milnacipran, venlafaxine, bupropion, citalopram, tranylcypromine (particularly with certain diets), reboxetine, methylphenidate, clozapine, paliperidone, risperidone, buprenorphine+naloxone, memantine, galantamine, and rivastigmine. Conversely, 7 substances, namely amitriptyline, tranylcypromine, chlorprothixen, flupentixol, levomepromazine, olanzapine and trimipramine had the highest reported risk of low blood pressure ("very frequent"), and another 25 substances had the risk "frequent". No risk of hypertension or hypotension was documented for many other substances. Incidentally, we observed that the reported effects on blood pressure for single substances (e. g. citalopram) markedly differed between the SmPCs from different manufacturers, rendering a clear risk assessment impossible for many medications. Discussion According to the German SmPc, many psychiatric medications are associated with the risk of arterial hypertension and, even more so, hypotension. We hardly observed substance group effects, such as high blood pressure with noradrenergic antidepressants. Commonly used tables summarising secondary causes of arterial hypertension should be revised in terms of psychiatric medications. Our rank orders of risk may aid choosing the best psychiatric medications in patients with known hypertension or at risk for syncope, as well as when blood pressure changes occur under psychiatric pharmacotherapy. A definitive risk assessment however requires controlled studies.

Combined treatment with ipilimumab and intratumoral interleukin-2 in pretreated patients with stage IV melanoma-safety and efficacy in a phase II study.

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.

Comparative Characterization Study of a LaBr3(Ce) Scintillation Crystal in Two Surface Wrapping Scenarios: Absorptive and Reflective.

The properties of a 50 mm × 50 mm × 30 mm monolithic LaBr3:Ce scintillator crystal coupled to a position-sensitive multi-anode photomultiplier (PMT, Hamamatsu H9500), representing the absorbing detector of a Compton camera under study for online ion (proton) beam range verification in hadron therapy, was evaluated in combination with either absorptive or reflective crystal surface coating. This study covered an assessment of the energy and position-dependent energy resolution, exhibiting a factor of 2.5-3.5 improvement for the reflectively wrapped crystal at 662 keV. The spatial dependency was investigated using a collimated (137)Cs source, showing a steep degradation of the energy resolution at the edges and corners of the absorptively wrapped crystal. Furthermore, the time resolution was determined to be 273 ps (FWHM) and 536 ps (FWHM) with reflective and absorptive coating, respectively, using a (60)Co source. In contrast, the light spread function (LSF) of the light amplitude distribution on the PMT segments improved for the absorptively wrapped detector. Both wrapping modalities showed almost no differences in the energy-dependent photopeak detection efficiency.

Hospital use of systemic antifungal drugs: a multi-center surveillance update from Germany.

BACKGROUND: The consumption of antifungal agents increased over the last decade, resulting in the development of resistant organisms and causing a significant pharmaco economic burden. Antifungal drugs are widely used for the treatment of systemic fungal infections and high-risk patients, especially with severe hematological or oncological conditions. Up to date, there are no reliable and systematically reported data on the consumption of antifungal substances on a nationwide level available. The presented study gives an update to the previously published multicenter study investigating antifungal consumption in different settings from five university hospital centers in Germany from 2001 to 2003. METHODS: Consumption data for systemic antifungal drugs were obtained through the hospital pharmacies for 2001-2003 and 2008-2011 regarding the medical and surgical services of five university hospital centers in Germany (A-E). Drug use densities were calculated as yearly RDDs/100 patient days. These calculations were performed for the surgical and medical services, and independently for surgical and medical ICUs, as well as for the hematology-oncology services. RESULTS: We report an increased utilization of systemic antifungal drugs in both study periods. The mean drug use density (mean value of all 5 hospitals) in the medical services increased by 24% between 2001 and 2003. In 2011, this value was 37% above the level from 2001 (12.4 RDD/100 patient days in 2001, 15.4 RDD/100 patient days in 2003, 17.0 RDD/100 patient days in 2011). The 4-year average drug use density (2008-2011) of medical services ranged between 11.6 RDD/100 patient days (hospital E) and 23.8 RDD/100 patient days (hospital A). Drug use densities were in medical intensive care units 29.4 RDD/100 patient days and hematology-oncology services 49.9 RDD/100 patient days. CONCLUSIONS: Despite the variability of the prescribing patterns between the tertiary hospitals, the presented pharmaco-epidemiological data are a cornerstone for the initiation and implementation of effective antifungal stewardship programmes and might serve as important benchmarking information for other hospitals with similar structures and baseline settings.

Intravenous zanamivir for patients with pneumonitis due to pandemic (H1N1) 2009 influenza virus.

We report on 2 critically ill patients with pneumonitis and acute respiratory distress syndrome due to pandemic (H1N1) 2009 influenza A virus who were treated with intravenous zanamivir and had favorable clinical outcomes. Zanamivir given intravenously may be a therapeutic option in patients with critical illness and mechanical ventilation.

Amiloride-sensitive nasal potential difference is not changed by estradiol and progesterone replacement but relates to BPD or death in a randomized trial on preterm infants.

Postnatal replacement of placental estradiol (E2) and progesterone (P) in preterm infants may improve lung function, possibly mediated through enhanced epithelial Na(+) transport and alveolar fluid clearance. Preterm infants of <29 wk gestational age and <1000 g birth weight requiring mechanical ventilation within 12 h of birth were randomized to receive either 2.5 mg/kg E2 and 22.5 mg/kg P per day (E2/P), or vehicle placebo. Epithelial Na(+) transport was assessed in 29 infants by measuring total nasal potential difference (NPD) and amiloride-sensitive NPD (ASNPD) on postnatal days of life 1, 3, 5, and 7, and mean values of all four measurements were calculated. Bronchopulmonary dysplasia (BPD) was defined as need for supplemental oxygen (goal Sa(O2) 90%) or mechanical ventilation at 36 wk corrected postmenstrual age. Mean ASNPD was -6.5 +/- 2.8 mV in infants receiving E2/P and -6.1 +/- 2.6 mV in infants receiving placebo (not significant). NPD was -10.6 +/- 3.8 mV and -10.7 +/- 3.6 mV, respectively. The ASNPD was significantly higher in infants surviving without BPD (-7.1 +/- 2.5 mV) than in infants developing BPD or not surviving (-5.2 +/- 2.4 mV). In conclusion, ASNPD is not changed by postnatal replacement of E2 and P. Infants at high risk of developing BPD had lower ASNPD values in the immediate postnatal period.

Prenatal estrogen and progesterone deprivation impairs alveolar formation and fluid clearance in newborn piglets.

Exposure to high levels of estradiol (E2) and progesterone (P) derived from the fetoplacentomaternal unit during the last trimester of pregnancy may play a crucial role in prenatal lung development and immediate postnatal alveolar fluid clearance (AFC). To measure prenatal alveolar formation and postnatal amiloride-sensitive AFC after pharmacological deprivation of E2 and P in utero, fetuses from five sows received an intramuscular depot injection of the E2 receptor blocker ICI 182.780 (ICI) and the P receptor blocker RTI 3021-022 (RTI) and fetuses of five other sows received a placebo injection (control group) during a laparotomy at 90 d of gestation (term gestation, 115 d). Piglets were delivered by cesarean section on d 114 of gestation. Of 95 live-born piglets, 35 were mechanically ventilated. The airways of the right lower lobe were isolated by a balloon catheter wedged in the bronchus and 5% albumin in 0.9% NaCl with or without 1 mmol/L amiloride was instilled. Amiloride-sensitive AFC was calculated from the protein concentration changes in fluid recovered after 120 min as the percentage of absorbed fluid. Lungs were removed under standardized conditions to perform alveolar counts. Prenatal treatment with ICI and RTI resulted in a significantly lower amiloride-sensitive AFC (median, 31%; min-max, -4-58) than placebo (74%, 18-231). Median alveolar counts per visual field were significantly lower in piglets that were exposed to ICI and RTI (38, 21-78) compared with placebo (56, 32-113). We conclude that prenatal E2 and P deprivation significantly impaired alveolar formation and amiloride-sensitive AFC.

Hospital use of systemic antifungal drugs.

BACKGROUND: Sales data indicate a major increase in the prescription of antifungal drugs in the last two decades. Many new agents for systemic use that only recently have become available are likely to be prescribed intensively in acute care hospitals. Sales data do not adequately describe the developments of drug use density. Given the concerns about the potential emergence of antifungal drug resistance, data on drug use density, however, may be valuable and are needed for analyses of the relationship between drug use and antifungal resistance. METHODS: Hospital pharmacy records for the years 2001 to 2003 were evaluated, and the number of prescribed daily doses (PDD, defined according to locally used doses) per 100 patient days were calculated to compare systemic antifungal drug use density in different medical and surgical service areas between five state university hospitals. RESULTS: The 3-year averages in recent antifungal drug use for the five hospitals ranged between 8.6 and 29.3 PDD/100 patient days in the medical services (including subspecialties and intensive care), and between 1.1 and 4.0 PDD/100 patient days in the surgical services, respectively. In all five hospitals, systemic antifungal drug use was higher in the hematology-oncology service areas (mean, 48.4, range, 24 to 101 PDD/100 patient days, data for the year 2003) than in the medical intensive care units (mean, 18.3, range, 10 to 33 PDD/100) or in the surgical intensive care units (mean, 10.7, range, 6 to 18 PDD/100). Fluconazole was the most prescribed antifungal drug in all areas. In 2003, amphotericin B consumption had declined to 3 PDD/100 in the hematology-oncology areas while voriconazole use had increased to 10 PDD/100 in 2003. CONCLUSION: Hematology-oncology services are intense antifungal drug prescribing areas. Fluconazole and other azol antifungal drugs are the most prescribed drugs in all patient care areas while amphotericin B use has considerably decreased. The data may be useful as a benchmark for focused interventions to improve prescribing quality.

Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial.

BACKGROUND & AIMS: Antibiotic prophylaxis in necrotizing pancreatitis remains controversial. Until now, there have been no double-blind studies dealing with this topic. METHODS: A total sample size of 200 patients was calculated to demonstrate with a power of 90% that antibiotic prophylaxis reduces the proportion of patients with infected pancreatic necrosis from 40% placebo (PLA) to 20% ciprofloxacin/metronidazole (CIP/MET). One hundred fourteen patients with acute pancreatitis in combination with a serum C-reactive protein exceeding 150 mg/L and/or necrosis on contrast-enhanced CT scan were enrolled and received either intravenous CIP (2 x 400 mg/day) + MET (2 x 500 mg/day) or PLA. Study medication was discontinued and switched to open antibiotic treatment when infectious complications, multiple organ failure sepsis, or systemic inflammatory response syndrome (SIRS) occurred. After half of the planned sample size was recruited, an adaptive interim analysis was performed, and recruitment was stopped. RESULTS: Fifty-eight patients received CIP/MET and 56 patients PLA. Twenty-eight percent in the CIP/MET group required open antibiotic treatment vs. 46% with PLA. Twelve percent of the CIP/MET group developed infected pancreatic necrosis compared with 9% of the PLA group (P = 0.585). Mortality was 5% in the CIP/MET and 7% in the PLA group. In 76 patients with pancreatic necrosis on contrast-enhanced CT scan, no differences in the rate of infected pancreatic necrosis, systemic complications, or mortality were observed. CONCLUSIONS: This study detected no benefit of antibiotic prophylaxis with respect to the risk of developing infected pancreatic necrosis.

Calcium and phosphorus balance of extremely preterm infants with estradiol and progesterone replacement.

Infants born extremely prematurely are deprived of the placental supply of estradiol (E2) and progesterone (Prog) at an earlier developmental stage compared to an infant born at term. We hypothesized that the retention of Ca (calcium) and P (phosphorus) would be improved by an E2 and Prog replacement. Twenty female infants with a mean gestational age of 26.6 weeks (+/-1.5 SD) and a mean birth weight of 744 g (+/-156) were enrolled in a randomized controlled pilot study. One group received an E2 and Prog replacement to maintain intrauterine plasma concentrations of E2 and Prog and the other group served as control. When intake of formula was at least 100 mL/kg/d, a 3-day Ca and P balance study was performed. Ca and P intake was increased individually until both elements were excreted in the urine. The mean Ca and P retention was 4.21 (+/-1.75) mMol/kg/d (58% of intake) and 2.66 (+/-1.01) mMol/kg/d (80%) in the replaced group and 3.39 (+/-1.69) mMol/kg/d (56%) and 2.03 (+/-0.79) mMol/kg/d (71%) in the control group, respectively. In this pilot study the retention of Ca and P was not improved by an E2 and Prog replacement.

Growth of the uterus and mammary glands and vaginal cytologic features in extremely premature infants with postnatal replacement of estradiol and progesterone.

OBJECTIVE: Growth of the uterus and the mammary glands and changes in vaginal cytologic features are known to be estrogen dependent and were evaluated to proof the biologic effectiveness of a postnatal replacement of estradiol and progesterone in extremely premature infants. STUDY DESIGN: Thirty female infants with a mean gestational age of 26.4 weeks (24.1-28.7 weeks) and a mean birth weight of 708 g (370-990 g) were investigated. Fifteen infants received postnatal replacement of estradiol and progesterone for 6 weeks to maintain intrauterine plasma levels of estradiol and progesterone. Uterine size and the diameter of mammary glands were assessed repeatedly by ultrasound scans and palpation. Vaginal smears were also obtained. RESULTS: The uterus and mammary glands showed significant growth during the hormone replacement, but growth was not observed in nontreated infants. Vaginal smears showed high karyopyknotic and eosinophilic indices in both groups at birth; the indices remained significantly higher at 3 and 6 weeks in the hormone-treated infants. CONCLUSION: The biologic effectiveness of postnatal estradiol and progesterone replacement in extremely premature infants was proved.