Safety and clinical activity of durvalumab combined with tremelimumab in recurrent/metastatic head and neck squamous cell carcinoma: a multicenter phase I study.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741). METHODS: In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS: A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts. CONCLUSIONS: Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.

Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.

BACKGROUND: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here. PATIENTS AND METHODS: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK). RESULTS: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively. CONCLUSIONS: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

Anexelekto (AXL) no more: microRNA-155 (miR-155) controls the "Uncontrolled" in SARS-CoV-2.

AXL is the gene that encodes the Anexelekto (AXL) receptor tyrosine kinase that demonstrates significant roles in various cellular processes, including cell growth, survival, and migration. Anexelekto is a Greek word meaning excessive and uncontrolled, semantically implying the crucial involvement of AXL in cancer and immune biology, and in promoting cancer metastasis. AXL overexpression appears to drive epithelial to mesenchymal transition, tumor angiogenesis, decreased antitumor immune response, and resistance to therapeutic agents. Recently, AXL has been reported to play important roles in several viral infections, including SARS-CoV-2. We have previously outlined the importance of microRNAs (miRNAs, miRs) and especially miR-155 in SARS-CoV-2 pathophysiology through regulation of the Renin-Angiotensin Aldosterone System (RAAS) and influence on several aspects of host innate immunity. MiRNAs are negative regulators of gene expression, decreasing the stability of target RNAs or limiting their translation and, enthrallingly, miR-155 is also involved in AXL homeostasis-both endogenously and pharmaceutically using repurposed drugs (e.g., metformin)-highlighting thrifty evolutionary host innate immunity mechanisms that successfully can thwart viral entry and replication. Cancer, infections, and immune system disturbances will increasingly involve miRNA diagnostics and therapeutics in the future.

Live to die another day: novel insights may explain the pathophysiology behind smoker's paradox in SARS-CoV-2 infection.

The severe acute respiratory coronavirus 2 (SARS-CoV-2) infection demonstrates a highly variable and unpredictable course. Several reports have claimed a smoker's paradox in coronavirus disease 2019 (COVID-19), in line with previous suggestions that smoking is associated with better survival after acute myocardial infarction and appears protective in preeclampsia. Several plausible physiological explanations exist accounting for the paradoxical observation of smoking engendering protection against SARS-CoV-2 infection. In this review, we delineate novel mechanisms whereby smoking habits and smokers' genetic polymorphism status affecting various nitric oxide (NO) pathways (endothelial NO synthase, cytochrome P450 (CYP450), erythropoietin receptor (EPOR); ß-common receptor (ßcR)), along with tobacco smoke modulation of microRNA-155 and aryl-hydrocarbon receptor (AHR) effects, may be important determinators of SARS-CoV-2 infection and COVID-19 course. While transient NO bioavailability increase and beneficial immunoregulatory modulations through the above-mentioned pathways using exogenous, endogenous, genetic and/or therapeutic modalities may have direct and specific, viricidal SARS-CoV-2 effects, employing tobacco smoke inhalation to achieve protection equals self-harm. Tobacco smoking remains the leading cause of death, illness, and impoverishment.

Beauty and the beast: host microRNA-155 versus SARS-CoV-2.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection in the young and healthy usually results in an asymptomatic or mild viral syndrome, possibly through an erythropoietin (EPO)-dependent, protective evolutionary landscape. In the old and in the presence of co-morbidities, however, a potentially lethal coronavirus disease 2019 (COVID-19) cytokine storm, through unrestrained renin-angiotensin aldosterone system (RAAS) hyperactivity, has been described. Multifunctional microRNA-155 (miR-155) elevation in malaria, dengue virus (DENV), the thalassemias, and SARS-CoV-1/2, plays critical antiviral and cardiovascular roles through its targeted translational repression of over 140 genes. In the present review, we propose a plausible miR-155-dependent mechanism whereby the translational repression of AGRT1, Arginase-2 and Ets-1, reshapes RAAS towards Angiotensin II (Ang II) type 2 (AT2R)-mediated balanced, tolerable, and SARS-CoV-2-protective cardiovascular phenotypes. In addition, it enhances EPO secretion and endothelial nitric oxide synthase activation and substrate availability, and negates proinflammatory Ang II effects. Disrupted miR-155 repression of AT1R + 1166C-allele, significantly associated with adverse cardiovascular and COVID-19 outcomes, manifests its decisive role in RAAS modulation. BACH1 and SOCS1 repression creates an anti-inflammatory and cytoprotective milieu, robustly inducing antiviral interferons. MiR-155 dysregulation in the elderly, and in comorbidities, allows unimpeded RAAS hyperactivity to progress towards a particularly aggressive COVID-19 course. Elevated miR-155 in thalassemia plausibly engenders a favorable cardiovascular profile and protection against malaria, DENV, and SARS-CoV-2. MiR-155 modulating pharmaceutical approaches could offer novel therapeutic options in COVID-19.

Ferrite based antennae for launching Alfvén waves.

Whistler and Alfvén waves are known to scatter mirror-trapped electrons and protons into the loss cone of the earth's dipole magnetic field. An array of satellites with properly phased antennas can be used to artificially reduce the flux of energetic particles from regions where their flux has been naturally or artificially pumped. In any space based system, the power required to drive antennas is at a premium. We present here experimental evidence that the efficiency of an antenna can be greatly enhanced with the use of ferrite cores with high relative magnetic permeability µ. Ferrite-based antennas were constructed to launch Alfvén waves in a magnetized plasma. The wave magnetic field of shear Alfvén waves launched with a ferrite core was by the magnetization factor µ larger than that of a similar antenna without a ferrite. Combining multiple ferrite antennas allowed control of the injected perpendicular wavelength. This novel technique can be used to efficiently launch low frequency waves with amplitude above the threshold required for nonlinear triggering.

A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours.

BACKGROUND: ARQ 087 is an orally administered pan-FGFR inhibitor with multi-kinase activity. This Phase 1 study evaluated safety, pharmacokinetics, and pharmacodynamics of ARQ 087 and defined the recommended Phase 2 dose (RP2D). METHODS: Patients with advanced solid tumours received ARQ 087 administered initially at 25 mg every other day and dose-escalated from 25 to 425 mg daily (QD) continuous dosing. FGF19, 21, 23, and serum phosphate were assessed as potential biomarkers of target engagement. RESULTS: 80 patients were enrolled, 61 in dose-escalation/food-effect cohorts and 19 with pre-defined tumour types in the expansion cohort. The most common ARQ 087-related adverse events were fatigue (49%), nausea (46%), aspartate aminotransferase (AST) increase (30%), and diarrhoea (23%). Four patients (5%) experienced grade 1 treatment-related hyperphosphataemia. Dose-limiting toxicity was reversible grade 3 AST increase. The RP2D was 300 mg QD. Pharmacokinetics were linear and dose-proportional from 25 to 325 mg QD, and were unaffected by food. Statistically significant changes (P-value<0.05) suggest phosphate and FGF19 levels as markers of target engagement. In 18 evaluable patients with FGFR genetic alterations, 3 confirmed partial responses (two intrahepatic cholangiocarcinomas (iCCA) with FGFR2 fusions and one urothelial cancer with FGFR2 and FGF19 amplification) and two durable stable disease at ⩾16 weeks with tumour reduction (FGFR2 fusion-positive iCCA and adrenocortical carcinoma with FGFR1 amplification) were observed. CONCLUSIONS: ARQ 087 had manageable toxicity at the RP2D of 300 mg QD, showed pharmacodynamics effects, and achieved objective responses, notably in patients with FGFR2 genetic alterations.

The Predictive Value of the Syntax Score in Patients With Chronic Coronary Artery Disease Undergoing Percutaneous Coronary Intervention or Coronary Artery Bypass Grafting: A Pilot Study.

OBJECTIVES: To evaluate the usefulness of the SYNTAX score (SS) in predicting 1-year clinical outcomes in a population of patients with chronic coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). BACKGROUND: Despite the proven prognostic value of the SS in patients with multivessel and/or left main (LM) CAD, its usefulness in other patient subsets remains uncertain. METHODS: This was a prospective single centre cohort study conducted from September 2012 to November 2014 at the Nicosia General Hospital, Cyprus. Patients (n=140; 94% men and 6% women) with chronic CAD undergoing revascularization with either PCI or CABG were evaluated. RESULTS: At 1-year, angina occurred in 20 patients (14.3%), myocardial infarction (MI) in 3 patients (2.1%), repeat revascularization procedures in 9 patients (6.4%) and death in 12 patients (8.6%). The SS independently predicted angina (p=0.024) but was not predictive of MI (p=0.964), death (p=0.292) or repeat revascularization (p=0.069). CONCLUSION: In this patient population, the SS predicted angina in the year following revascularization but was not predictive of MI, death or repeat revascularization.

First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin's lymphomas.

BACKGROUND: To evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of copanlisib, a phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors or non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Phase I dose-escalation study including patients with advanced solid tumors or NHL, and a cohort of patients with type 2 diabetes mellitus. Patients received three weekly intravenous infusions of copanlisib per 28-day cycle over the dose range 0.1-1.2 mg/kg. Plasma copanlisib levels were analyzed for pharmacokinetics. Biomarker analysis included PIK3CA, KRAS, BRAF, and PTEN mutational status and PTEN immunohistochemistry. Whole-body [(18)F]-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) was carried out at baseline and following the first dose to assess early pharmacodynamic effects. Plasma glucose and insulin levels were evaluated serially. RESULTS: Fifty-seven patients received treatment. The MTD was 0.8 mg/kg copanlisib. The most frequent treatment-related adverse events were nausea and transient hyperglycemia. Copanlisib exposure was dose-proportional with no accumulation; peak exposure positively correlated with transient hyperglycemia post-infusion. Sixteen of 20 patients treated at the MTD had reduced (18)FDG-PET uptake; 7 (33%) had a reduction >25%. One patient achieved a complete response (CR; endometrial carcinoma exhibiting both PIK3CA and PTEN mutations and complete PTEN loss) and two had a partial response (PR; both metastatic breast cancer). Among the nine NHL patients, all six with follicular lymphoma (FL) responded (one CR and five PRs) and one patient with diffuse large B-cell lymphoma had a PR by investigator assessment; two patients with FL who achieved CR (per post hoc independent radiologic review) were on treatment >3 years. CONCLUSION: Copanlisib, dosed intermittently on days 1, 8, and 15 of a 28-day cycle, was well tolerated and the MTD was determined to be 0.8 mg/kg. Copanlisib exhibited dose-proportional pharmacokinetics and promising anti-tumor activity, particularly in patients with NHL. CLINICALTRIALSGOV: NCT00962611; https://clinicaltrials.gov/ct2/show/NCT00962611.

LLLT for the management of patients with ankylosing spondylitis.

This study aimed to compare the effectiveness of the combined low-level laser therapy (LLLT) and passive stretching with combined placebo LLLT laser and the same passive stretching exercises in patients suffering from Αnkylosing spondylitis. Forty-eight patients suffering from Αnkylosing spondylitis participated in the study and were randomized into two groups. Group A (n = 24) was treated with a λ = 820 Ga-Al-As laser CW, with power intensity = 60 mW/cm(2), energy per point in each session = 4.5 J, total energy per session = 27.0 J, in contact with specific points technique, plus passive stretching exercises. Group B (n = 24), received placebo laser plus the same passive stretching exercises. Both groups received 12 sessions of laser or placebo within 8 weeks; two sessions per week (weeks 1-4) and one session per week (weeks 5-8). Pain and function scales were completed before the treatment, at the end of the fourth and eighth week of treatment, and 8 weeks after the end of treatment (follow-up). Group A revealed a significant improvement after 8 weeks of treatment in all pain and function scales. At 8-week follow-up, the improvement remained only for the pain, while for all other function outcomes the differences were not statistically significant. The results suggested that after an 8-week treatment and after a follow-up, the combination of LLLT and passive stretching exercises decreased pain more effectively than placebo LLLT along with the same passive stretching exercises in patients with Αnkylosing spondylitis. Future studies are needed to establish the relative and absolute effectiveness of the above protocol.

A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors.

BACKGROUND: Fibroblast growth factors (FGFs) play important roles in multiple cancers by supporting tumor growth and angiogenesis. FP-1039 (GSK3052230) is a FGF ligand trap consisting of the extracellular domain of FGF receptor 1 (FGFR1) fused with the Fc region of IgG1. FP-1039 binds and neutralizes multiple FGFs that normally bind FGFR1. The primary objective of this phase I study was to evaluate the safety and tolerability of FP-1039. PATIENTS AND METHODS: Eligible patients with metastatic or locally advanced solid tumors for which standard treatments were ineffective were treated with weekly doses of FP-1039 for 4 weeks, followed by 2 weeks observation. RESULTS: Thirty-nine subjects received a mean of 6 infusions of FP-1039 at doses ranging from 0.5 to 16 mg/kg weekly, with no maximally tolerated dose identified. Grade 3 or greater treatment emergent adverse events were uncommon. Four dose-limiting toxicities were reported at doses of 0.75 mg/kg (urticaria), 1 mg/kg (intestinal perforation and neutropenia), and 16 mg/kg (muscular weakness). Drug exposure was dose proportional, and the terminal elimination half-life was 2.6-3.9 days following a single dose. Target engagement as measured by low free plasma FGF2 levels was achieved. FGF pathway dysregulation was uncommon. No objective responses were observed. CONCLUSION: In nonselected cancer patients with advanced disease, treatment with FP-1039 was well tolerated and toxicities associated with small molecule drugs that inhibit FGFR tyrosine kinases, including hyperphosphatemia, were not observed. Further studies of FP-1039 in patients selected for FGF pathway dysregulation, who are most likely to benefit, are now underway.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Phase I ficlatuzumab monotherapy or with erlotinib for refractory advanced solid tumours and multiple myeloma.

BACKGROUND: Ficlatuzumab, a humanised hepatocyte growth factor (HGF) IgG1κ inhibitory monoclonal antibody, was evaluated for recommended phase II dose (RP2D), safety, pharmacokinetics (PKs), antidrug antibody (ADA), pharmacodynamics (PDs) and antitumour activity as monotherapy or combined with erlotinib. METHODS: Patients with solid tumours received ficlatuzumab 2, 5, 10 or 20 mg kg(-1) intravenously every 2 weeks (q2w). Additional patients were treated at the RP2D erlotinib. RESULTS: Forty-one patients enrolled at doses ⩽20 mg kg(-1). Common adverse events (AEs) included peripheral oedema, fatigue and nausea. Three patients experienced grade ⩾3 treatment-related hyperkalaemia/hypokalaemia, diarrhoea or fatigue. Best overall response (44%) was stable disease (SD); median duration was 5.5 months (0.4-18.7 months). One patient has been on therapy with SD for >4 years. Pharmacokinetics of ficlatuzumab showed low clearance (0.17-0.26 ml h(-1) kg(-1)), a half-life of 6.8-9.4 days and dose-proportional exposure. Ficlatuzumab/erlotinib had no impact on the PK of either agent. No ADAs were detected. Ficlatuzumab increased serum HGF levels. CONCLUSIONS: Recommended phase II dose is 20 mg kg(-1) q2w for ficlatuzumab monotherapy or with erlotinib. Preliminary antitumour activity and manageable AEs were observed. Pharmacokinetics were dose-proportional and consistent with other IgG therapeutics. Ficlatuzumab was not immunogenic, and serum HGF was a potential PD marker.

Assessment of chondrogenic differentiation potential of autologous activated peripheral blood stem cells on human early osteoarthritic cancellous tibial bone scaffold.

INTRODUCTION: Current therapeutic regimens in osteoarthritis (OA) address mainly pain but not the slow progressive degradation of the extracellular matrix (ECM) and the loss of a chondrogenic phenotype in articular cartilage. In the present study, using an early OA cancellous bone scaffold, we aimed to uncover evidence of the successful hyaline cartilage regenerative capacity of autologous human granulocyte colony-stimulating factor (hG-CSF)-activated peripheral blood stem cells (AAPBSC) with growth factor addition. MATERIALS AND METHODS: AAPBSC were harvested in ten patients (median age 58 years, 8 females), and flow cytometry was performed for cell surface markers. Arthroscopically obtained cancellous bone scaffold specimens were seeded with AAPBSC. In Group 1, the scaffold was seeded with AAPBSC only, in Group 2, AAPBSC plus hyaluronic acid (HA), and in Group 3, AAPBSC plus HA, hG-CSF, and double-centrifuged platelet-rich plasma (PRP). The specimens were analyzed for cell attachment and proliferation by the fluorometric quantification of cellular DNA assay and scanning electron microscopy. Chondrogenic gene expression was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) of Sox9, collagen type II (COL-2), and aggrecan. Histological sections of scaffold constructs for cartilaginous matrix formation were stained with toluidine blue (proteoglycan) and safranin O (sGAG) after 3 weeks. RESULTS: AAPBSC displayed especially high levels of CD29 and CD44 surface markers, as well as CD90, and CD105, while only a small proportion expressed CD34. Almost half of the seeded cells attached on the bone scaffolds in all three groups (not statistically significant), whereas the means of cell proliferation on day 7 compared to day 1 were statistically significant difference with the order of increase as group 3 > group 2 > group 1. RT-PCR showed statistically significant sequential increases in Sox9, COL-2, and Aggrecan all being highest in group 3. Histological analysis demonstrated cells in the cancellous bone scaffold with a round morphology, and ECM was positively stained by toluidine blue and safranin O indicating increased proteoglycan and glycosaminoglycan content, respectively, in the newly formed cartilage matrix. CONCLUSIONS: AAPBSC initiated chondrocyte differentiation on an autologous cancellous bone scaffold, and the addition of PRP and hG-CSF further stimulated cell proliferation toward a chondrocyte phenotype with potentiated Sox9 transcription resulting in sequential COL-2 and aggrecan mRNA increases that ultimately resulted in histologically confirmed increased proteoglycan and glucosaminoglycan content in newly formed hyaline cartilage.

Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1. RESULTS: Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities. CONCLUSION: Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

Soybean oil: a potentially new intravascular perfusate.

BACKGROUND: Given that micelles of lipids are colloids, the hypothesis was generated that the rapid administration of large volumes of soybean oil micelles would be an effective perfusion fluid. We also hypothesized that oxygen loading would be enhanced due to the greater solubility of oxygen in lipids compared to water. METHODS: A 100% lethal mouse model of blood loss was used to compare the ability of soybean oil micelles to that of Ringer's lactate, blood and other fluids, with respect to raising and maintaining the blood pressure for one hour. Oxygen on- and off-loading of various concentrations of soybean oil micelles was determined using mass spectroscopy. Nitric oxide uptake by micelles was also determined in a similar fashion. RESULTS: A 20% soybean oil emulsion was superior to Ringer's lactate in raising and maintaining blood pressure. A 20% soybean oil emulsion with 5% albumin added was superior to shed blood as well as solutions comprised of 5% albumin added to either normal saline or Ringer's lactate. There was a linear relationship between oxygen content and micelle concentration between 10% and 30%. Off-loading of oxygen from the micelles was nearly as fast as off-loading from water. Nitric oxide also loaded preferentially onto soybean oil micelles. CONCLUSIONS: (1) Soybean oil emulsions were superior to other fluids in restoring and maintaining the blood pressure; (2) oxygen-carrying ability of soybean oil micelles exceeds that of water and follows Henry's law between 10% and 30% w/v oil content; (3) nitric oxide was carried by the micelles; (4) animals receiving soybean oil micelles did not exhibit fat embolization; (5) colloids comprised of soybean oil-containing micelles may be used to replace blood loss and may be used to deliver oxygen and other potentially therapeutic gases such as nitric oxide to tissues.