Pharmacokinetic enhancers (boosters) are compounds used in combination with a primary therapeutic agent (drug) and are not used for their direct effects on the disease but because they enhance or ...restore the activity of the primary agent. Hence, in certain cases, they represent an indispensable escort for enzyme-labile drugs. Pharmacokinetic enhancers can exert their activity on different ways. In the most common case, they inhibit enzymes such as human cytochrome P450 enzymes in the liver or other organs and, thereby, block or reduce undesired metabolism and inactivation of the primary drug. In this review, an overview will be given on the therapeutically most important classes of pharmacokinetic enhancers like β-lactamase inhibitors, inhibitors of CYP (cytochrome P450) enzymes in HIV therapy and hepatitis C, boosters for fluoropyrimidine-type anticancer agents, compounds utilized for enabling therapy of Parkinson's disease with levodopa, and others. Inhibitors of efflux pumps in both pathogenic bacteria and tumor cells will be addresses shortly.
BackgroundLymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ...ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab.MethodsEligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D).ResultsIn total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline.ConclusionsIeramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.Trial registration numberNCT02460224.
The devastating root-knot nematode
can cause severe damage to field and greenhouse crops. Due to high economic losses, alternative products are essential to replace banned or strictly regulated ...nematicides that affect human health and/or the environment. Garlic based products have been previously investigated as environmentally friendly nematicides and their active substances, diallyl polysulfides exist as formulated nematicides on the market. We tested the garlic-based nematicide NEMguard
DE as protective of tomato roots. In vitro evaluation of the lethal concentration (LC) showed strong nematicidal activity with LC
of 0.8 mg/mL after 96 h and LC
of 1.5 mg/mL. NEMguard
DE showed protective effect against
as a single application in small pots and a second application further reduced root galling, significantly. Large greenhouse trials were carried out in two consecutive years to test single and monthly applications of NEMguard
DE. In both years, no controlling effect could be observed on
. We assume that the silt content of the loamy sandy soil used had an effect on the polysulfides, inhibiting their nematicidal effect. We conclude that further experiments are necessary to investigate the nematicidal potential of NEMguard
DE under different soil compositions or as a different formulation.
Young children with brain tumours are at high risk of developing treatment-related sequelae. We aimed to assess neuropsychological outcomes 5 years after treatment. This cross-sectional study ...included children under 4 years of age with medulloblastoma (MB) or ependymoma (EP) enrolled in the German brain tumour trials HIT2000 and HIT-REZ2005. Testing was performed using the validated Wuerzburg Intelligence Diagnostics (WUEP-D), which includes Kaufman-Assessment-Battery, Coloured Progressive Matrices, Visual-Motor Integration, finger tapping "Speed", and the Continuous Performance Test. Of 104 patients in 47 centres, 72 were eligible for analyses. We assessed whether IQ was impacted by disease extent, disease location, patient age, gender, age at surgery, and treatment (chemotherapy with our without craniospinal irradiation CSI or local radiotherapy LRT). Median age at surgery was 2.3 years. Testing was performed at a median of 4.9 years after surgery. Patients with infratentorial EPs (treated with LRT) scored highest in fluid intelligence (CPM 100.9±16.9, mean±SD); second best scores were achieved by patients with MB without metastasis treated with chemotherapy alone (CPM 93.9±13.2), followed by patients with supratentorial EPs treated with LRT. In contrast, lowest scores were achieved by patients that received chemotherapy and CSI, which included children with metastasised MB and those with relapsed MB M0 (CPM 71.7±8.0 and 73.2±21.8, respectively). Fine motor skills were reduced in all groups. Multivariable analysis revealed that type of treatment had an impact on IQ, but essentially not age at surgery, time since surgery or gender. Our results confirm previous reports on the detrimental effects of CSI in a larger cohort of children. Comparable IQ scores in children with MB treated only with chemotherapy and in children with EP suggest that this treatment strategy represents an attractive option for children who have a high chance to avoid application of CSI. Longitudinal follow-up examinations are warranted to assess long-term neuropsychological outcomes.
Atorvastatin calcium (Lipitor
®
, Sortis
®
) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be ...sensitive to acid treatment, but only little data has been published on the structures of the degradation products. Here we report the identification of two novel degradation products of atorvastatin, which are formed only under drastic acidic conditions. While treatment with conc. sulfuric acid led to a loss of the carboxanilide residue (accompanied by an expectable lactonization/dehydration process in the side chain), treatment with conc. aqueous hydrochloric acid gave a complex, bridged molecule under C–C-bond formation of the lactone moiety with the pyrrole, migration of the isopropyl group and loss of the carboxanilide residue. The novel degradation products were characterized by NMR spectroscopy, HRMS data and X-ray crystal structure analysis.
BackgroundImmunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like ...SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models showed promising results on T cell activation and migration in combination with immune checkpoint inhibition.MethodsHere, we describe the successful application of anti-CXCL12 (NOX-A12) in patients with advanced stage pretreated metastatic colorectal and pancreatic cancer (OPERA trial). The treatment consisted of 2 weeks of anti-CXCL12 monotherapy with NOX-A12 followed by combination therapy with pembrolizumab (n=20 patients) until progression or intolerable toxicity had occurred.ResultsThe treatment was safe and well tolerated with 83.8% grade I/II, 15.5% grade III and 0.7% grade V adverse events. Of note, for a majority of patients, time on trial treatment was prolonged compared with their last standard treatment preceding trial participation. Systematic serial biopsies revealed distinct patterns of modulation. Tissue and clinical responses were associated with Th1-like tissue reactivity upon CXCL12 inhibition. A downregulation of a cytokine cassette of interleukin (IL)-2/IL-16/CXCL-10 was associated with tumor resistance and furthermore linked to a rare, CXCL12-associated CD14+CD15+promonocytic population. T cells showed aggregation and directed movement towards the tumor cells in responding tissues. Serum analyses detected homogeneous immunomodulatory patterns in all patients, regardless of tissue responses.ConclusionsWe demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies.
Resveratrol as well as caloric restriction were shown to extend lifespan in some model organisms and may possibly delay onset of ageing-related diseases in humans. Yet, resveratrol supplementation ...does not always extend lifespan of animal models or improve health status of humans. Because of interindividual differences in human microbiota, resveratrol metabolite production in the gut differs. While some individuals produce lunularin and dihydroresveratrol in their gut, others produce dihydroresveratrol only. Therefore, we addressed the question whether these metabolites differ in their biological impact on ageing and intraperitoneally injected 13-month-old C57BL/6JRj mice on an ad-libitum (AL) HFD with resveratrol, dihydroresveratrol or lunularin (24 mg/kg bodyweight; 3 times/week). Compared to mice injected with vehicle (AL-control), resveratrol and dihydroresveratrol did not change bodyweight and had no impact on insulin or glucose levels while lunularin slightly reduced feed intake and bodyweight gain. CR-mice showed lowered cholesterol, insulin and leptin levels, elevated adiponectin and phosphorylated AMPK levels in liver as well as increased transcription of Pck1 and Pgc1α when compared to the AL-control. In contrast, injections with the test substances did not change these parameters. We therefore conclude that in our model, resveratrol, lunularin and dihydroresveratrol did not act as CR mimetics.
Infections with Herpes simplex virus (HSV)-1 or -2 usually present as mild chronic recurrent disease, however in rare cases can result in life-threatening conditions with a large spectrum of ...pathology. Monoclonal antibody therapy has great potential especially to treat infections with virus resistant to standard therapies. HDIT101, a humanized IgG targeting HSV-1/2 gB was previously investigated in phase 2 clinical trials. The aim of this study was to develop a next-generation therapy by combining different antiviral monoclonal antibodies.
A lymph-node derived phage display library (LYNDAL) was screened against recombinant gB from Herpes simplex virus (HSV) -1 and HDIT102 scFv was selected for its binding characteristics using bio-layer interferometry. HDIT102 was further developed as fully human IgG and tested alone or in combination with HDIT101, a clinically tested humanized anti-HSV IgG, in vitro and in vivo. T-cell stimulating activities by antigen-presenting cells treated with IgG-HSV immune complexes were analyzed using primary human cells. To determine the epitopes, the cryo-EM structures of HDIT101 or HDIT102 Fab bound to HSV-1F as well as HSV-2G gB protein were solved at resolutions < 3.5 Å.
HDIT102 Fab showed strong binding to HSV-1F gB with Kd of 8.95 × 10
M and to HSV-2G gB with Kd of 3.29 × 10
M. Neutralization of cell-free virus and inhibition of cell-to-cell spread were comparable between HDIT101 and HDIT102. Both antibodies induced internalization of gB from the cell surface into acidic endosomes by binding distinct epitopes in domain I of gB and compete for binding. CryoEM analyses revealed the ability to form heterogenic immune complexes consisting of two HDIT102 and one HDIT101 Fab bound to one gB trimeric molecule. Both antibodies mediated antibody-dependent phagocytosis by antigen presenting cells which stimulated autologous T-cell activation. In vivo, the combination of HDIT101 and HDIT102 demonstrated synergistic effects on survival and clinical outcome in immunocompetent BALB/cOlaHsd mice.
This biochemical and immunological study showcases the potential of an effective combination therapy with two monoclonal anti-gB IgGs for the treatment of HSV-1/2 induced disease conditions.
Multiple therapeutic monoclonal antibodies (mAbs) are currently under development or in (pre)clinical study phases to reach regulatory approval. Among these, a new mAb against herpes simplex virus, ...HDIT101, was recently tested in healthy volunteers during a phase I clinical trial (first-in-human, dose escalation). In the frame of the pharmacokinetic evaluation of this new therapy, a mass spectrometric (MS)-based method was developed for the quantification of HDIT101 in human plasma using liquid chromatography coupled to tandem mass spectrometry. In this work, we describe the development of this bioanalytical assay using the quantification of a HDIT101 surrogate peptide, the assay validation procedure according to the FDA guidelines within the calibration range from 20 to 5000 μg/mL, and its application to plasma samples from the first-in-human clinical trial. This work presents a generic workflow for the development of MS-based quantification assays of new therapeutic antibodies that allows reaching high immunopurification recovery (>98% for HDIT101 over the full calibration range with a precision of 6.9% CV). Surrogate peptide and stable isotopically labeled internal standard were stable, and batch-to-batch accuracies and precisions at the four quality standard levels ranged between −2 and 5% bias and 8 and 11% CV, respectively.
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