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International Journal of Molecular... Nov 2023The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols... (Review)
Review
The design of clinical protocols and the selection of drugs with appropriate posology are critical parameters for therapeutic outcomes. Optimal therapeutic protocols could ideally be designed in all diseases including for millions of patients affected by excess iron deposition (EID) toxicity based on personalised medicine parameters, as well as many variations and limitations. EID is an adverse prognostic factor for all diseases and especially for millions of chronically red-blood-cell-transfused patients. Differences in iron chelation therapy posology cause disappointing results in neurodegenerative diseases at low doses, but lifesaving outcomes in thalassemia major (TM) when using higher doses. In particular, the transformation of TM from a fatal to a chronic disease has been achieved using effective doses of oral deferiprone (L1), which improved compliance and cleared excess toxic iron from the heart associated with increased mortality in TM. Furthermore, effective L1 and L1/deferoxamine combination posology resulted in the complete elimination of EID and the maintenance of normal iron store levels in TM. The selection of effective chelation protocols has been monitored by MRI T2* diagnosis for EID levels in different organs. Millions of other iron-loaded patients with sickle cell anemia, myelodysplasia and haemopoietic stem cell transplantation, or non-iron-loaded categories with EID in different organs could also benefit from such chelation therapy advances. Drawbacks of chelation therapy include drug toxicity in some patients and also the wide use of suboptimal chelation protocols, resulting in ineffective therapies. Drug metabolic effects, and interactions with other metals, drugs and dietary molecules also affected iron chelation therapy. Drug selection and the identification of effective or optimal dose protocols are essential for positive therapeutic outcomes in the use of chelating drugs in TM and other iron-loaded and non-iron-loaded conditions, as well as general iron toxicity.
Topics: Humans; Deferiprone; Deferoxamine; Pyridones; Iron Chelating Agents; Iron Overload; Chelation Therapy; Iron; beta-Thalassemia; Drug Therapy, Combination
PubMed: 38069073
DOI: 10.3390/ijms242316749 -
Scientific Reports Oct 2023Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export...
Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkBα compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3Kδ in CLL.
Topics: Animals; Mice; Leukemia, Lymphocytic, Chronic, B-Cell; Cell Line, Tumor; Antineoplastic Agents; Hydrazines; Drug Combinations; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37805613
DOI: 10.1038/s41598-023-44039-0 -
The Journal of Hospital Infection Apr 2024Candida auris is an emerging multidrug-resistant yeast which can cause severe infection in hospitalized patients. Since its first detection in 2009, C. auris has spread...
BACKGROUND
Candida auris is an emerging multidrug-resistant yeast which can cause severe infection in hospitalized patients. Since its first detection in 2009, C. auris has spread globally. The control and elimination of this pathogen in a hospital setting is particularly challenging because of its ability to form biofilms, allowing for long-term patient colonization and persistence in the environment. Identification of C. auris from cultures is difficult due to the morphologic similarities to other yeasts, its slow growth, and the low culture sensitivity when using standard agars and temperatures.
AIM
We have developed a screening protocol for C. auris colonization using an in-house-developed polymerase chain reaction (PCR), combined with confirmatory culture in optimized conditions.
METHODS
C. auris-specific primers and probe were developed, targeting the internal transcribed spacer (ITS) region, and specificity was confirmed in silico using the BLAST tool. The PCR was validated using a panel of 12 C. auris isolates and 103 isolates from 22 other Candida species and was shown to be 100% accurate. The limit of detection of the assay was determined at approximately four cells per PCR.
FINDINGS
C. auris screening was introduced on February 15, 2023, and was used for patients who had been admitted to a healthcare facility abroad in the two months prior to admission to our hospital. The screening protocol included swabs from nose, throat, rectum, axilla, and groin. In the first eight months, 199 patients were screened and seven were found positive (4%).
CONCLUSION
Our proposed screening protocol may contribute to control C. auris in hospitals.
Topics: Humans; Candidiasis; Candida auris; Candida; Yeasts; Antifungal Agents; Microbial Sensitivity Tests
PubMed: 38286238
DOI: 10.1016/j.jhin.2023.12.019 -
BMC Infectious Diseases Nov 2023The urgent need for new treatments for multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is evident. However, the...
Study protocol for safety and efficacy of all-oral shortened regimens for multidrug-resistant tuberculosis: a multicenter randomized withdrawal trial and a single-arm trial [SEAL-MDR].
INTRODUCTION
The urgent need for new treatments for multidrug-resistant tuberculosis (MDR-TB) and pre-extensively drug-resistant tuberculosis (pre-XDR-TB) is evident. However, the classic randomized controlled trial (RCT) approach faces ethical and practical constraints, making alternative research designs and treatment strategies necessary, such as single-arm trials and host-directed therapies (HDTs).
METHODS
Our study adopts a randomized withdrawal trial design for MDR-TB to maximize resource allocation and better mimic real-world conditions. Patients' treatment regimens are initially based on drug resistance profiles and patient's preference, and later, treatment-responsive cases are randomized to different treatment durations. Alongside, a single-arm trial is being conducted to evaluate the potential of sulfasalazine (SASP) as an HDT for pre-XDR-TB, as well as another short-course regimen without HDT for pre-XDR-TB. Both approaches account for the limitations in second-line anti-TB drug resistance testing in various regions.
DISCUSSION
Although our study designs may lack the internal validity commonly associated with RCTs, they offer advantages in external validity, feasibility, and ethical appropriateness. These designs align with real-world clinical settings and also open doors for exploring alternative treatments like SASP for tackling drug-resistant TB forms. Ultimately, our research aims to strike a balance between scientific rigor and practical utility, offering valuable insights into treating MDR-TB and pre-XDR-TB in a challenging global health landscape. In summary, our study employs innovative trial designs and treatment strategies to address the complexities of treating drug-resistant TB, fulfilling a critical gap between ideal clinical trials and the reality of constrained resources and ethical considerations.
TRAIL REGISTRATION
Chictr.org.cn, ChiCTR2100045930. Registered on April 29, 2021.
Topics: Humans; Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Clinical Protocols; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 38012543
DOI: 10.1186/s12879-023-08644-8 -
International Journal of Molecular... Jul 2023The aim of our laboratory-based study was to investigate the extent of delayed-onset cell death after cryopreservation in endothelial and epithelial cell lines of...
The aim of our laboratory-based study was to investigate the extent of delayed-onset cell death after cryopreservation in endothelial and epithelial cell lines of ovarian origin. We found differences in percentages of vital cells directly after warming and after cultivation for 48 to 72 h. A granulosa cell line of endothelial origin (KGN) and an epithelial cell line (OvCar-3) were used. In both DMSO-containing and DMSO-free protocols, significant differences in vitality rates between the different cell lines when using open and closed vitrification could be shown (DMSO-containing: KGN open vs. OvCar open, = 0.001; KGN closed vs. OvCar closed, = 0.001; DMSO-free: KGN open vs. OvCar open, = 0.001; KGN closed vs. OvCar closed, = 0.031). Furthermore, there was a marked difference in the percentage of vital cells immediately after warming and after cultivation for 48 to 72 h; whereas the KGN cell line showed a loss of cell viability of 41% using a DMSO-containing protocol, the OvCar-3 cell loss was only 11% after cultivation. Using a DMSO-free protocol, the percentages of late-onset cell death were 77% and 48% for KGN and OvCar-3 cells, respectively. Our data support the hypothesis that cryopreservation-induced damage is cell type and cryoprotective agent dependent.
Topics: Female; Humans; Apoptosis; Cell Line, Tumor; Ovarian Neoplasms; Cryopreservation; Cryoprotective Agents; Granulosa Cells; Dimethyl Sulfoxide
PubMed: 37569601
DOI: 10.3390/ijms241512225 -
PloS One 2023Behavioural and psychological symptoms of dementia (BPSD) should only rarely and briefly be treated with antipsychotics. Despite recommendations to the contrary, the use...
INTRODUCTION
Behavioural and psychological symptoms of dementia (BPSD) should only rarely and briefly be treated with antipsychotics. Despite recommendations to the contrary, the use of antipsychotics in nursing home residents with dementia is widespread and followed by serious adverse effects. Intervention studies on methods to reduce the use of antipsychotics in persons with dementia are few and needed. The aim of this protocol is to describe the rationale and content of the intervention DEprescribing and Care to reduce Antipsychotics in DEmentia (DECADE)-a hybrid effectiveness-implementation pilot study.
MATERIALS AND METHODS
This is a protocol of a prospective hybrid effectiveness-implementation pilot study. The primary aim of DECADE is to reduce the use of antipsychotic drugs by 50% in 50% of nursing home residents with dementia while maintaining or improving BPSD. The intervention is implemented in six nursing homes including approximately 190 residents with dementia and consists of Academic Detailing, medication review, education of nursing home staff, and care plans. The evaluation of feasibility and potential effectiveness is an overall assessment of all clinical and process outcomes. Logistic regression analyses will be used to investigate factors characterizing situations with prescription of antipsychotics. BPSD is analysed with a before- and after design using self-controlled case series methods and the use of antipsychotics is analysed as interrupted time series.
DISCUSSION
This protocol describes a study that will provide an indication of DECADE effectiveness and a model for upscaling and further evaluation in a controlled design.
Topics: Humans; Antipsychotic Agents; Pilot Projects; Dementia; Deprescriptions; Prospective Studies
PubMed: 37943780
DOI: 10.1371/journal.pone.0294024 -
Biomaterials Dec 2023Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous...
Systemic injection of thrombolytic drugs is the gold standard treatment for non-invasive blood clot resolution. The most serious risks associated with the intravenous injection of tissue plasminogen activator-like proteins are the bleeding complication and the dose related neurotoxicity. Indeed, the drug has to be injected in high concentrations due to its short half-life, the presence of its natural blood inhibitor (PAI-1) and the fast hepatic clearance (0.9 mg/kg in humans, 10 mg/kg in mouse models). Overall, there is a serious need for a dose-reduced targeted treatment to overcome these issues. We present in this article a new acoustic cavitation-based method for polymer MBs synthesis, three times faster than current hydrodynamic-cavitation method. The generated MBs are ultrasound responsive, stable and biocompatible. Their functionalization enabled the efficient and targeted treatment of stroke, without side effects. The stabilizing shell of the MBs is composed of Poly-Isobutyl Cyanoacrylate (PIBCA), copolymerized with fucoidan. Widely studied for its targeting properties, fucoidan exhibit a nanomolar affinity for activated endothelium and activated platelets (P-selectins). Secondly, the thrombolytic agent (rtPA) was loaded onto microbubbles (MBs) with a simple adsorption protocol. Hence, the present study validated the in vivo efficiency of rtPA-loaded Fuco MBs to be over 50 % more efficient than regular free rtPA injection for stroke resolution. In addition, the relative injected rtPA grafted onto targeting MBs was 1/10th of the standard effective dose (1 mg/kg in mouse). As a result, no hemorrhagic event, BBB leakage nor unexpected tissue distribution were observed.
Topics: Humans; Animals; Mice; Tissue Plasminogen Activator; Microbubbles; Polymers; Fibrinolytic Agents; Stroke
PubMed: 37952499
DOI: 10.1016/j.biomaterials.2023.122385 -
Clinical and Translational Science Dec 2023Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8...
Protocol of the IntenSify-Trial: An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy.
Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.
Topics: Humans; Gemcitabine; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Cytostatic Agents; Deoxycytidine; Cobicistat; Antineoplastic Combined Chemotherapy Protocols; Paclitaxel; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Clinical Trials, Phase I as Topic
PubMed: 37920921
DOI: 10.1111/cts.13661 -
Frontiers in Molecular Biosciences 2023Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified... (Review)
Review
Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with genetic modifications for tumor selectivity, safety, and immunogenicity. Despite these modifications, HSV-1 OV immunotherapies are often treated with the same biosafety guidelines as the wild-type virus, potentially leading to reduced patient access and logistical hurdles for treatment centers, including community treatment centers and small group or private practices, and healthcare workers. Despite the lack of real-world evidence documenting possible transmission to close contacts, and in the setting of shedding and biodistribution analyses for T-VEC demonstrating limited infectivity and low risk of spread to healthcare workers, barriers to treatment with OV immunotherapies remain. With comprehensive information and educational programs, our hope is that updated biosafety guidance on OV immunotherapies will reduce logistical hurdles to ensure that patients have access to these innovative and potentially life-saving medicines across treatment settings. This work reviews a comprehensive collection of data in conjunction with the opinions of the authors based on their clinical experience to provide the suggested framework and key considerations for implementing biosafety protocols for OV immunotherapies, namely T-VEC, the only approved agent to date.
PubMed: 37795219
DOI: 10.3389/fmolb.2023.1178382 -
Bulletin of the World Health... Oct 2023The World Health Organization developed the Tricycle surveillance programme to obtain a global picture of antimicrobial resistance, especially in countries with limited...
The World Health Organization developed the Tricycle surveillance programme to obtain a global picture of antimicrobial resistance, especially in countries with limited surveillance capacity. The programme was developed within a One Health perspective. Tricycle provides a framework for applying a standardized technical protocol to determining the prevalence of extended-spectrum β-lactamase (ESBL)-producing in three sectors: the human, animal and environment sectors. Regular use of the protocol would enable information to be obtained on time trends and on inter- and intraregional variations, thereby generating dynamic data on antibacterial resistance for decision-makers. To date, 19 countries have begun implementing the Tricycle protocol, while other countries will start implementation in the coming years. The Network for Enhancing Tricycle ESBL Surveillance Efficiency (NETESE) was established to support countries implementing the Tricycle protocol. Currently, NETESE includes representatives from 15 institutions in eight low- or middle-income countries at different stages of Tricycle protocol implementation, and from four European countries involved in devising the protocol. This paper describes the Tricycle protocol, reports the initial experiences of NETESE participants with its implementation and discusses future challenges and opportunities.
Topics: Animals; Humans; Anti-Bacterial Agents; Escherichia coli Infections; beta-Lactamases; Drug Resistance, Bacterial; Escherichia coli
PubMed: 37772195
DOI: 10.2471/BLT.22.289520