Uric Acid Is a Genuine Metabolite of Penicillium cyclopium and Stimulates the Expression of Alkaloid Biosynthesis in This Fungus

On searching for endogenous, low-molecular-weight effectors of benzodiazepine alkaloid biosynthesis in Penicillium cyclopium uric acid was isolated from ethanolic or autoclaved mycelial extracts of this fungus. The isolation was based on a three-step high-pressure liquid chromatography procedure guided by a microplate bioassay, and uric acid was identified by mass spectrometry and the uricase reaction. Conidiospore suspensions that were treated with this compound during the early phase of outgrowth developed emerged cultures with an enhanced rate of alkaloid production. Uric acid treatment did not increase the in vitro measurable activity of the rate-limiting biosynthetic enzyme, cyclopeptine synthetase. However, these cultures displayed a reduced rate of uptake of the alkaloid precursor l-phenylalanine into the vacuoles of the hyphal cells as assayed in situ. It is suggested that the depressed capacity of vacuolar uptake caused by the contact of outgrowing spores with uric acid liberated from hyphal cells results in an enhanced availability of the precursor l-phenylalanine in the cytoplasm and thus accounts at least in part for the increase in alkaloid production

Efficiency and safety of inhalative sedation with sevoflurane in comparison to an intravenous sedation concept with propofol in intensive care patients: study protocol for a randomized controlled trial

Abstract Background State of the art sedation concepts on intensive care units (ICU) favor propofol for a time period of up to 72 h and midazolam for long-term sedation. However, intravenous sedation is associated with complications such as development of tolerance, insufficient sedation quality, gastrointestinal paralysis, and withdrawal symptoms including cognitive deficits. Therefore, we aimed to investigate whether sevoflurane as a volatile anesthetic technically implemented by the anesthetic-conserving device (ACD) may provide advantages regarding ‘weaning time’, efficiency, and patient’s safety when compared to standard intravenous sedation employing propofol. Method/Design This currently ongoing trial is designed as a two-armed, monocentric, randomized prospective phase II study including intubated intensive care patients with an expected necessity for sedation exceeding 48 h. Patients are randomly assigned to either receive intravenous sedation with propofol or sevoflurane employing the ACD. Primary endpoint is the comparison of the ‘weaning time’ defined as the time required from discontinuation of the sedating agent until sufficient spontaneous breathing occurs. Moreover, sedation depth evaluated by Richmond Agitation Sedation Scale and parameters of patient’s safety (that is, vital signs, laboratory monitoring of organ function) as well as the duration of mechanical ventilation and overall stay on the ICU are analyzed and compared. An intention-to-treat analysis will be carried out with all patients for whom it will be possible to define a wake-up time. In addition, a per-protocol analysis is envisaged. Completion of patient recruitment is expected by the end of 2012. Discussion This clinical study is designed to evaluate the impact of sevoflurane during long-term sedation of critically ill patients on ‘weaning time’, efficiency, and patient’s safety compared to the standard intravenous sedation concept employing propofol. Trial registration EudraCT2007-006087-30; ISCRTN90609144</p

Ramucirumab in combination with dacarbazine in patients with progressive well-differentiated metastatic pancreatic neuroendocrine tumors (RamuNET): study protocol for a multicenter single-arm trial

Background!#!Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients.!##!Methods!#!The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p &amp;lt; =p!##!Discussion!#!This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET.!##!Trial registration!#!EudraCT: 2017-001207-68 . Date of registration: 2018.01.03

Liver-HERO: hepatorenal syndrome-acute kidney injury (HRS-AKI) treatment with transjugular intrahepatic portosystemic shunt in patients with cirrhosis—a randomized controlled trial

Abstract Background Patients with cirrhosis and ascites (and portal hypertension) are at risk of developing acute kidney injury (AKI). Although many etiologies exist, hepatorenal AKI (HRS-AKI) remains a frequent and difficult-to-treat cause, with a very high mortality when left untreated. The standard of care is the use of terlipressin and albumin. This can lead to reversal of AKI, which is associated to survival. Nevertheless, only approximately half of the patients achieve this reversal and even after reversal patients remains at risk for new episodes of HRS-AKI. TIPS is accepted for use in patients with variceal bleeding and refractory ascites, which leads to a reduction in portal pressure. Although preliminary data suggest it may be useful in HRS-AKI, its use in this setting is controversial and caution is recommended given the fact that HRS-AKI is associated to cardiac alterations and acute-on-chronic liver failure (ACLF) which represent relative contraindications for transjugular intrahepatic portosystemic shunt (TIPS). In the last decades, with the new definition of renal failure in patients with cirrhosis, patients are identified at an earlier stage. These patients are less sick and therefore more likely to not have contraindications for TIPS. We hypothesize that TIPS could be superior to the standard of care in patients with HRS-AKI. Methods This study is a prospective, multicenter, open, 1:1-randomized, controlled parallel-group trial. The main end-point is to compare the 12-month liver transplant-free survival in patients assigned to TIPS compared to the standard of care (terlipressin and albumin). Secondary end-point include reversal of HRS-AKI, health-related Quality of Life (HrQoL), and incidence of further decompensation among others. Once patients are diagnosed with HRS-AKI, they will be randomized to TIPS or Standard of Care (SOC). TIPS should be placed within 72 h. Until TIPS placement, TIPS patients will be treated with terlipressin and albumin. Once TIPS is placed, terlipressin and albumin should be weaned off according to the attending physician. Discussion If the trial were to show a survival advantage for patients who undergo TIPS placement, this could be incorporated in routine clinical practice in the management of patients with HRS-AKI. Trial registration Clinicaltrials.gov NCT05346393 . Released to the public on 01 April 2022