Vitamin K1 pharmacokinetics in a clinical study and VKORC1 enzyme kinetics using HPLC methodology

The main objective of the present work by means of a phase I clinical study was to determine inter-individual variance in pharmacokinetics of intravenous and oral phylloquinone (vitamin K1) mixed micelles formulation in humans as well as to explore a possible effect of the VKORC1 promoter polymorphism c.-1639 G>A on the metabolism of phylloquinone. The pharmacokinetics of phylloquinone mixed micelles formulation (Konakion® MM 2 mg) were evaluated, in healthy human adult volunteers (n=30; 15 m, 15 f) using an open phase I design protocol upon oral and intravenous administration. The probands were subjected equally distributed (n=10; 5 m, 5 f) to three genotype-specific groups regarding VKORC1 promoter polymorphism c.-1639 G>A (GG, AG and AA) to explore their relationship to specific pharmacokinetic parameters. Phylloquinone serum levels were determined by reversed phase HPLC with fluorometric detection after post-column zinc reduction. The method proved to be highly accurate, robust and reliable and showed a limit of detection and quantification of 0.015 ng mL-1 and 0.15 ng mL-1, respectively. Measured phylloquinone serum concentrations were subjected to pharmacokinetic evaluation using a non-compartment analysis. Pharmacokinetic analysis of serum phylloquinone concentration versus time profiles revealed significant differences in main pharmacokinetic parameters. Significant inter-individual pharmacokinetic variance of vitamin K fate in the human body could be indicated. Further, an influence of the VKORC1 promoter polymorphism c.-1639 G>A on the pharmacokinetic properties of phylloquinone in humans was shown. Significant differences in main pharmacokinetic parameters such as bioavailability and terminal half-life between groups suggest corresponding differences in processing of vitamin K in the human body. The relevance of polymorphisms in CYP4F2 and ABCC6 in this regard must be further elucidated in an enlarged sampling. The clinical importance of potential genetic determinants of vitamin K status should be further investigated with respect to effects on absorption, distribution, metabolism and elimination of vitamin K. Furthermore, the enzymatic characteristics of the VKORC1 were examined by studying its enzyme kinetics. Comparing vitamin K1 and K2 as substrates and their apparent kinetic constants Km and Vmax, the binding affinity of vitamin K2 epoxide to the VKORC1 appears to be higher while vitamin K1 epoxide seems to bind in a weaker manner to the enzyme

Second-line and third-line therapy with nanoliposomal irinotecan (nal-IRI) in pancreatic cancer : a single-center experience and review of literature

Background: Prognosis of patients with pancreatic cancer is still extremely poor. First-line palliative therapies with FOLFIRINOX or gemcitabine/nab-paclitaxel have been established in the last decade. In the second-line, 5-FU/LV in combination with nanoliposomal irinotecan (nal-IRI) after gemcitabine has been shown to be effective. However, the use of nal-IRI as third-line therapy after FOLFIRINOX and gemcitabine-based chemotherapies is still controversial. In this study, we report about the use of 5-FU/LV + nal-IRI in a daily practice and analyze whether nal-IRI is an option as third-line therapy after FOLFIRINOX and gemcitabine/nab-paclitaxel. Methods: This is a single center retrospective analysis of patients with irresectable pancreatic cancer who were treated with 5-FU/LV and nal-IRI from 2017 to 2021 as second- or third-line palliative treatment. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed, and multivariate analysis was used to identify independent prognostic factors. Results: Twenty-nine patients receiving 5-FU/LV and nal-IRI were included in the analysis. The majority of patients (n=19) received 5-FU/nal-IRI as third-line therapy after pre-exposition to FOLFIRINOX and gemcitabine/nab-paclitaxel. Median OS and PFS were 9.33 months (95% CI: 3.37, 15.30) and 2.90 months (95% CI: 1.64, 4.16), respectively. Furthermore, patients receiving nal-IRI + 5-FU/LV as third-line treatment also showed some benefits, with no OS difference compared to second-line patients (9.33 vs. 10.27 months; HR: 1.85; 95% CI: 0.64, 5.41; P=0.253). Adverse effects were similar to reported trials. Conclusions: In our study, the use of 5-FU/nal-IRI in unselected patients with advanced pancreatic cancer showed similar OS, PFS and tolerance as randomized prospective phase II/III trials. Interestingly, the use of 5-FU/nal-IRI seemed to be beneficial in third-line therapy, despite a pre-exposure to non-liposomal irinotecan

Automated quantitative evaluation of brain MRI may be more accurate for discriminating preterm born adults

Objective To investigate the structural brain abnormalities and their diagnostic accuracy through qualitative and quantitative analysis in term born and very preterm birth or with very low birth weight (VP/VLBW) adults. Methods We analyzed 3-T MRIs acquired in 2011–2013 from 67 adults (27 term born controls, mean age 26.4 years, 8 females; 40 VP/VLBWs, mean age 26.6 years, 16 females). We compared automatic segmentations of the white matter, deep gray matter and cortical gray matter, manual corpus callosum measurements and visual ratings of the ventricles and white matter with t tests, logistic regression, and receiver operator characteristic (ROC) curves. Results Automatic segmentation correctly classified 84% of cases; visual ratings correctly classified 63%. Quantitative volumetry based on automatic segmentation revealed higher ventricular volume, lower posterior corpus callosum, and deep gray matter volumes in VP/VLBW subjects compared to controls (p < 0.01). Visual rating and manual measurement revealed a thinner corpus callosum in VP/VLBW adults (p = 0.04) and deformed lateral ventricles (p = 0.03) and tendency towards more “dirty” white matter (p = 0.06). Automatic/manual measures combined with visual ratings correctly classified 87% of cases. Stepwise logistic regression identified three independent features that correctly classify 81% of cases: ventricular volume, deep gray matter volume, and white matter aspect. Conclusion Enlarged and deformed lateral ventricles, thinner corpus callosum, and “dirty” white matter are prevalent in preterm born adults. Their visual evaluation has low diagnostic accuracy. Automatic volume quantification is more accurate but time consuming. It may be useful to ask for prematurity before initiating further diagnostics in subjects with these alterations

Increased impairment of cerebral autoregulation in COVID-19 associated pulmonary failure requiring extracorporeal membrane oxygenation

IntroductionCerebrovascular complications are feared but also commonly reported in patients with COVID-19 requiring extracorporeal membrane oxygenation (ECMO) support therapy. Besides other reasons, a connection between impaired cerebral autoregulation and SARS-CoV-2 infection as a mechanism for an increase in cerebrovascular complications has been hypothesized.MethodsIn an observational single-center study, we investigated a cohort of 48 patients requiring veno-venous ECMO support therapy with (n = 31) and without SARS-CoV-2 infection (n = 17). Cerebral autoregulation was assessed with the cerebral oximetry-derived autoregulation index (ORx) based on a moving correlation between arterial pressure and cerebral oximetry.ResultsPatients with ECMO support therapy and SARS-CoV-2 experienced more time with impaired cerebral autoregulation than without SARS-CoV-2 [17 ± 9 vs. 13 ± 9% (p = 0.027)]. Patients with SARS-CoV-2 suffering from cerebrovascular complications had more time with impaired autoregulation than non SARS-CoV-2 patients with these complications (19 ± 9 vs. 10 ± 4%, p = 0.032).ConclusionOur results suggest a connection between SARS-CoV-2 and impaired cerebral autoregulation as well as cerebrovascular complications in SARS-CoV-2 patients

Alteration of contrast enhanced ultrasound (CEUS) of hepatocellular carcinoma in patients with cirrhosis and transjugular intrahepatic portosystemic shunt (TIPS)

Abstract Transjugular intrahepatic portosystemic shunt (TIPS) can treat portal hypertensive complications and modifies hepatic hemodynamics. Modification of liver perfusion can alter contrast enhancement dynamics of liver nodules. This study investigated the diagnostic performance of contrast-enhanced ultrasound (CEUS) to diagnose hepatocellular carcinoma (HCC) in cirrhosis with TIPS. In this prospective monocentric observational study, CEUS was used to characterize focal liver lesions in patients at risk for HCC with and without TIPS. Times of arterial phase hyperenhancement (APHE) und washout were quantified. Perfusion-index (PI) and resistance-index (RI) of hepatic artery and portal venous flow parameters were measured via doppler ultrasonography. Diagnostic gold standard was MRI/CT or histology. This study included 49 liver lesions [23 TIPS (11 HCC), 26 no TIPS (15 HCC)]. 26 were diagnosed as HCC by gold standard. Sensitivity and specificity of CEUS to diagnose HCC with and without TIPS were 93.3% and 100% vs. 90.9% and 93.3%, respectively. APHE appeared significantly earlier in patients with TIPS compared to patients without TIPS. TIPS significantly accentuates APHE of HCC in CEUS. CEUS has good diagnostic performance for diagnosis of HCC in patients with TIPS

Oncolytic virotherapy - can a poliovirus cure cancer?

IntroductionOncolytic virotherapy is a promising form of gene therapy for cancer, using already existing “natural” agents - viruses. Tumor resistance to a lot of drugs after intensive chemotherapy is considered to be the main obstacle in curing cancer patients. Recent studies have shown that oncolytic viruses demonstrate a potential for effective treatment in a variety of cancer patients.AimThe aim of this work is to investigate the possible curative effect of the oncolytic poliovirus (PVS-RIPO) in patients with glioblastoma multiforme. Material and methodsPVS-RIPO is a genetically engineered polio virus which is infused directly into the patient`s tumor. Once inside the tumor, PVS-RIPO infects and kills tumor cells. PVS-RIPO consists of a genetically modified non-pathogenic version of the oral poliovirus Sabin type 1. Although this tumor cell killing alone may have tumor-fighting results, the likely key to therapy with PVS-RIPO is its ability to recruit the patients’ immune response against the cancer.ResultsThe researchers have already achieved remarkable results in trials on animals, and may be on the verge of a completely new treatment for people. Currently, Phase I clinical trials of PVS-RIPO against glioblastoma are ongoing. For now this treatment is showing promising results by extending the life expectancy of patients with recurrent glioblastoma multiforme.ConclusionEverything in the world of cancer treatment develops extremely fast these days. The key to better cancer treatment is a better understanding of the disease and the mechanisms that may work to fight it

Acute medical units during the first wave of the COVID-19 pandemic: a cross-national exploratory study of impact and responses

10.7861/clinmed.2021-0150CLINICAL MEDICINE215E462-E46

Systematic review and meta‐analysis on non‐opioid analgesics in palliative medicine

Abstract Non‐opioid analgesics are widely used for pain relief in palliative medicine. However, there is a lack of evidence‐based recommendations addressing the efficacy, tolerability, and safety of non‐opioids in this field. A comprehensive systematic review and meta‐analysis on current evidence can provide a basis for sound recommendations in clinical practice. A database search for controlled trials on the use of non‐opioids in adult palliative patients was performed in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE from inception to 18 February 2018. Endpoints were pain intensity, opioid‐sparing effects, safety, and quality of life. Studies with similar patients, interventions, and outcomes were included in the meta‐analyses. Our systematic search was able to only identify studies dealing with cancer pain. Of 5991 retrieved studies, 43 could be included (n = 2925 patients). There was no convincing evidence for satisfactory pain relief by acetaminophen alone or in combination with strong opioids. We found substantial evidence of moderate quality for a satisfactory pain relief in cancer by non‐steroidal anti‐inflammatory drugs (NSAIDs), flupirtine, and dipyrone compared with placebo or other analgesics. There was no evidence for a superiority of one specific non‐opioid. There was moderate quality of evidence for a similar pain reduction by NSAIDs in the usual dosage range compared with up to 15 mg of morphine or opioids of equianalgesic potency. The combination of NSAID and step III opioids showed a beneficial effect, without a decreased tolerability. There is scarce evidence concerning the combination of NSAIDs with weak opioids. There are no randomized‐controlled studies on the use of non‐opioids in a wide range of end‐stage diseases except for cancer. Non‐steroidal anti‐inflammatory drugs, flupirtine, and dipyrone can be recommended for the treatment of cancer pain either alone or in combination with strong opioids. The use of acetaminophen in the palliative setting cannot be recommended. Studies are not available for long‐term use. There is a lack of evidence regarding pain treatment by non‐opioids in specific cancer entities

A systematic review on the role of vitamins, minerals, proteins, and other supplements for the treatment of cachexia in cancer: a European Palliative Care Research Centre cachexia project

We provide a systematic review to support the European Palliative Care Research Collaboration development of clinical guidelines for cancer patients suffering from cachexia. CENTRAL, MEDLINE, PsycINFO, ClinicalTrials.gov, and a selection of cancer journals have been searched up until 15 April 2016. The systematic literature research yielded 4214 publications with 21 of these included in the final evaluation. Regarding minerals, our search identified only one study examining the use of magnesium with no effect on weight loss. As far as vitamins are concerned, vitamin E in combination with omega-3 fatty acids displayed an effect on survival in a single study, vitamin D showed improvement of muscle weakness in prostate cancer patients, and vitamin C supplementation led to an improvement of various quality of life aspects in a sample with a variety of cancer diagnoses. For proteins, a combination therapy of β-hydroxy-β-methylbutyrate (HMB), arginine, and glutamine showed an increase in lean body mass after 4 weeks in a study of advanced solid tumour patients, whereas the same combination did not show a benefit on lean body mass in a large sample of advanced lung and other cancer patients after 8 weeks. L-carnitine led to an increase of body mass index and an increase in overall survival in advanced pancreatic cancer patients. Adverse effects of food supplementation were rare and showed mild intensity. There is not enough solid evidence for the use of minerals, vitamins, proteins, or other supplements in cancer. No serious adverse effects have been reported with dietary supplementation