Hydroxychloroquine as Prophylaxis for COVID-19: A Review

The impact of the COVID-19 pandemic worldwide has led to a desperate search for effective drugs and vaccines. There are still no approved agents for disease prophylaxis. We thus decided to use a drug repositioning strategy to perform a state-of-the-art review of a promising but controversial drug, hydroxychloroquine (HCQ), in an effort to provide an objective, scientific and methodologically correct overview of its potential prophylactic role. The advantage of using known drugs is that their toxicity profile is well known and there are fewer commercial interests (e.g., expired patents), thus allowing the scientific community to be freer of constraints. The main disadvantage is that the economic resources are almost always insufficient to promote large multinational clinical trials. In the present study, we reviewed the literature and available data on the prophylactic use of HCQ. We also took an in-depth look at all the published clinical data on the drug and examined ongoing clinical trials (CTs) from the most important CT repositories to identify a supporting rationale for HCQ prophylactic use. Our search revealed a substantial amount of preclinical data but a lack of clinical data, highlighting the need to further assess the translational impact of in vitro data in a clinical setting. We identified 77 CTs using a multiplicity of HCQ schedules, which clearly indicates that we are still far from reaching a standard of care. The majority of the CTs (92%) are randomized and 53% are being conducted in a phase 3 or 2/3 setting. The comparator is placebo or control in 55 (77%) of the randomized studies. Forty-eight (62%) CTs expect to enroll up to 1,000 subjects and 50 (71%) plan to recruit healthcare workers (HCW). With regard to drug schedules, 45 (58.5%) CTs have planned a loading dose, while 18 (23.4%) have not; the loading dose is 800 mg in 19 trials (42.2%), 400 mg in 19 (42.2%), 600 mg in 4 (8.9%) and 1,200 mg in 1 (2.2%). Forty trials include at least one daily schedule, while 19 have at least one weekly schedule. Forty-one (53.2%) will have a treatment duration of more than 30 days. Awaiting further developments that can only derive from the results of these prospective randomized CTs, the take-home message of our review is that a correct methodological approach is the key to understanding whether prophylactic HCQ can really represent an effective strategy in preventing COVID-19.

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Testing Strategies of the In Vitro Micronucleus Assay for the Genotoxicity Assessment of Nanomaterials in BEAS-2B Cells

Nanomaterials ◽

10.3390/nano11081929 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1929

Author(s):

Tereza Cervena ◽

Andrea Rossnerova ◽

Tana Zavodna ◽

Jitka Sikorova ◽

Kristyna Vrbova ◽

...

Keyword(s):

Cytochalasin B ◽

Culture Media ◽

Methodological Approach ◽

Micronucleus Assay ◽

Toxicity Testing ◽

In Vitro Toxicity ◽

Testing Strategies ◽

Transmission Electron ◽

The Impact

The evaluation of the frequency of micronuclei (MN) is a broadly utilised approach in in vitro toxicity testing. Nevertheless, the specific properties of nanomaterials (NMs) give rise to concerns regarding the optimal methodological variants of the MN assay. In bronchial epithelial cells (BEAS-2B), we tested the genotoxicity of five types of NMs (TiO2: NM101, NM103; SiO2: NM200; Ag: NM300K, NM302) using four variants of MN protocols, differing in the time of exposure and the application of cytochalasin-B combined with the simultaneous and delayed co-treatment with NMs. Using transmission electron microscopy, we evaluated the impact of cytochalasin-B on the transport of NMs into the cells. To assess the behaviour of NMs in a culture media for individual testing conditions, we used dynamic light scattering measurement. The presence of NMs in the cells, their intracellular aggregation and dispersion properties were comparable when tests with or without cytochalasin-B were performed. The genotoxic potential of various TiO2 and Ag particles differed (NM101 < NM103 and NM302 < NM300K, respectively). The application of cytochalasin-B tended to increase the percentage of aberrant cells. In conclusion, the comparison of the testing strategies revealed that the level of DNA damage induced by NMs is affected by the selected methodological approach. This fact should be considered in the interpretation of the results of genotoxicity tests.

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Use of placebo in cancer medicine: The experience of a National Clinical Trials organization

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6104 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6104-6104

Author(s):

J. L. Pater ◽

W. Parulekar

Keyword(s):

Clinical Trials ◽

Supportive Care ◽

Study Design ◽

Standard Of Care ◽

Phase Iii ◽

Design Data ◽

Standard Of Care Treatment ◽

Prevention Trials ◽

The Impact ◽

Phase Iii Studies

6104 Background: The use of placebos in cancer clinical trials requires careful evaluation. Factors that must be considered include the impact of placebo on endpoint measurement, the efficacy of placebo relative to standard of care treatment, patient altruism/acceptance of a non-active intervention and the resulting increase in complexity of study conduct with respect to randomization, drug supply, data management, analysis and the unblinding process. Methods: We reviewed the experience of the National Cancer Institute of Canada Clinical Trials Group with the use of placebo in the randomized phase III setting from 1982–2005. Results: Since 1982, 34 studies were identified that utilized a placebo as part of study design. Data is presented below according to the type of study and date of study activation. The numbers in brackets represent those studies in which placebo was used alone in the control arm. Supportive care studies were the most common type of study employing a placebo as part of study design and constituted almost 50% of our Group’s experience. Therapeutic studies involving placebo were conducted in multiple sites including breast (4), lung (6), myeloma (1), melanoma (1), ovary (1) and pancreas (1). Conclusion: Phase III studies involving a placebo constitute an important part of our clinical trial activity and cross the spectrum of supportive care, therapeutic and prevention trials. The use of placebo in cancer studies may increase due to the relative ease of blinding in studies that evaluate targeted, oral therapies with minimal toxicities as well as the need for unbiased assessment of increasingly used endpoints such as time to progression. [Table: see text] No significant financial relationships to disclose.

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Investigating the importance of individual mitochondrial genotype in susceptibility to drug-induced toxicity

Biochemical Society Transactions ◽

10.1042/bst20190233 ◽

2020 ◽

Vol 48 (3) ◽

pp. 787-797

Author(s):

Sophie L. Penman ◽

Alice S. Carter ◽

Amy E. Chadwick

Keyword(s):

Clinical Data ◽

Research Effort ◽

Personalised Medicine ◽

Current Evidence ◽

Mitochondrial Genetics ◽

Drug Induced ◽

Mitochondrial Haplogroup ◽

Mtdna Variation ◽

The Impact

The mitochondrion is an essential organelle responsible for generating cellular energy. Additionally, mitochondria are a source of inter-individual variation as they contain their own genome. Evidence has revealed that mitochondrial DNA (mtDNA) variation can confer differences in mitochondrial function and importantly, these differences may be a factor underlying the idiosyncrasies associated with unpredictable drug-induced toxicities. Thus far, preclinical and clinical data are limited but have revealed evidence in support of an association between mitochondrial haplogroup and susceptibility to specific adverse drug reactions. In particular, clinical studies have reported associations between mitochondrial haplogroup and antiretroviral therapy, chemotherapy and antibiotic-induced toxicity, although study limitations and conflicting findings mean that the importance of mtDNA variation to toxicity remains unclear. Several studies have used transmitochondrial cybrid cells as personalised models with which to study the impact of mitochondrial genetic variation. Cybrids allow the effects of mtDNA to be assessed against a stable nuclear background and thus the in vitro elucidation of the fundamental mechanistic basis of such differences. Overall, the current evidence supports the tenet that mitochondrial genetics represent an exciting area within the field of personalised medicine and drug toxicity. However, further research effort is required to confirm its importance. In particular, efforts should focus upon translational research to connect preclinical and clinical data that can inform whether mitochondrial genetics can be useful to identify at risk individuals or inform risk assessment during drug development.

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The impact of the inclusion of clinical data review on overall radiographic response and progression in oncology clinical trials as assessed by blinded independent central review

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.6511 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 6511-6511

Author(s):

N. Wangler ◽

K. Borradaile ◽

R. Ford

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Clinical Trials ◽

Clinical Review ◽

Clinical Data ◽

Study Endpoint ◽

Primary Study ◽

Best Response ◽

Oncology Clinical Trials ◽

The Impact

6511 Background: The United States Food and Drug Administration (USFDA) advocates blinded independent central review (BICR) of radiographic exams for oncology registration studies when the primary study endpoint is based on tumor measurements, such as progression-free survival, time to progression or objective response rate. However, a proportion of subjects progress clinically prior to radiographic evidence of disease progression and in certain indications, measurement of cutaneous lesions may be incorporated into response criteria calculations. Methods: BICR data from 4,183 subjects in the following indications: lymphoma, melanoma, breast cancer, and colorectal cancer, was blinded, pooled, and reviewed to determine the impact of clinical review on best response and date of progression following BICR of radiographic images. Results: Inclusion of clinical data and/or clinical photography impacted 27% (47/171) of lymphoma subjects, affecting the assessment of the best response (13%), best response date (16%) and/or the date of progression (19%); 12% (13/107) of melanoma subjects, affecting the assessment of the best response (6%), best response date (5%), and/or the date of progression (8%); 10% (308/2,947) of breast cancer subjects, affecting the assessment of the best response (4%), best response date (4%), and/or the date of progression (9%); 3% (32/958) of colorectal cancer subjects, affecting the assessment of the best response (2%), best response date (2%), and/or the date of progression (2%). Conclusions: When using BICR to determine endpoints in oncology clinical trials, inclusion of a clinical review may be relevant in 27% of subjects for lymphoma, 12% for melanoma, 10% for breast cancer, and 3% for colorectal cancer. [Table: see text]

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Impact of organ function based standard exclusion criteria in diffuse large b-cell lymphoma (DLBCL) patients: Who gets left behind?

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e14100 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e14100-e14100

Author(s):

Arushi Khurana ◽

Raphael Mwangi ◽

Grzegorz S. Nowakowski ◽

Thomas Matthew Habermann ◽

Stephen M. Ansell ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

B Cell Lymphoma ◽

Standard Of Care ◽

Trial Participation ◽

Newly Diagnosed ◽

Organ Function ◽

Exclusion Criteria ◽

The Us ◽

The Impact

e14100 Background: Only 3-5% of adult cancer patients in the US enroll in clinical trials. Patients with organ dysfunction are often excluded from clinical trials, regardless of specific drug metabolism or relative function of the organ. The ASCO and the US FDA recommend modernizing criteria related to baseline organ function and comorbidities. In hematological malignancies, often the disease itself is the reason for organ function derangement. In order to better inform clinical trial eligibility and improve participation in the future, we evaluated the impact of baseline organ function on the potential eligibility for clinical trial enrollment for real world patients with newly diagnosed DLBCL. Methods: Consecutive, newly diagnosed lymphoma patients were offered enrollment from 2002-2015 into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence. This analysis is based on 1270 DLBCL patients receiving immunochemotherapy. Baseline organ function parameters were identified from the exclusion criteria for hemoglobin, absolute neutrophil count (ANC), platelet count, creatinine, and bilirubin reported in recent frontline trials in DLBCL (Table). Abstracted clinical labs from the MER were used to determine the percent of patients that would be excluded based on the criteria. Results: We determined that 11-23% of MER DLBCL patients receiving standard of care frontline therapy would have been excluded in the various trials utilizing baseline organ function alone (Table). Hemoglobin and renal function had the greatest impact on exclusion. Conclusions: Current national and international (phase II and III) trials are excluding up to 23% of patients from clinical trial participation based on organ function alone in DLBCL. These data will be useful in future clinical trial development to meet ASCO recommendations to increase trial accrual, while balancing the drug toxicities and patient safety. An online tool was developed based on these results to aid future trial development. [Table: see text]

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Caspofungin Acetate for Treatment of Invasive Fungal Infections

Annals of Pharmacotherapy ◽

10.1345/aph.1c114 ◽

2003 ◽

Vol 37 (1) ◽

pp. 90-98 ◽

Cited By ~ 34

Author(s):

Staci A Pacetti ◽

Steven P Gelone

Keyword(s):

Clinical Trials ◽

Invasive Aspergillosis ◽

Clinical Data ◽

Treatment Guidelines ◽

Fungal Infections ◽

Invasive Fungal Infections ◽

Current Therapy ◽

Candida Spp ◽

Fungal Cell

OBJECTIVE To briefly discuss the changing epidemiology of fungal infections and review currently available agents; provide a review of caspofungin; and discuss its pharmacology, pharmacokinetics, dosing guidelines, safety and efficacy, and role in the treatment of invasive fungal infections as it relates to current antifungal therapy. DATA SOURCES A MEDLINE (1966 to August 2002) database search using key words caspofungin, echino candins, fungal infections, and invasive aspergillosis, was completed to identify relevant articles including reviews, recent studies, treatment guidelines, and data from Merck and Company. STUDY SELECTION In vitro studies and all clinical trials were evaluated to summarize the clinical efficacy and safety of caspofungin. DATA SYNTHESIS The incidence of fungal infections is increasing as the population at risk expands. Cost, resistance, and morbidity and mortality are key issues. Adding to the antifungal armamentarium is necessary to address these therapeutic dilemmas. Caspofungin is the first member of a new class of antifungal agents, the echinocandins, to be approved for clinical use. Caspofungin is classified as a glucan synthase inhibitor and represents a class of agents with a novel mechanism of action. Unlike currently available agents (polyenes, pyrimidines, azoles) that exert their effect on the fungal cell membrane, the echinocandins are the first agents to inhibit fungal cell wall synthesis. Caspofungin exhibits activity against Aspergillus spp. and Candida spp., including non-albicans species. Data from clinical trials demonstrate that caspofungin is effective in patients with invasive aspergillosis as well as candida esophagitis. Its Food and Drug Administration–approved indication is limited to invasive aspergillosis refractory to or intolerant of current therapy. CONCLUSIONS Caspofungin has activity against Aspergillus spp. as well as a variety of Candida spp. Clinical data support its usefulness in the treatment of invasive aspergillosis and select candida infections. As additional clinical data become available, it seems likely that the therapeutic role of caspofungin will expand. THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT ACPE UNIVERSAL PROGRAM NUMBER: 407-000-03-001-H01

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Management of Optic Neuritis in Canada: Survey of Ophthalmologists and Neurologists

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s031716710000860x ◽

2008 ◽

Vol 35 (2) ◽

pp. 179-184 ◽

Cited By ~ 7

Author(s):

Edward J. Atkins ◽

Carolyn D. Drews-Botsch ◽

Nancy J. Newman ◽

Olivier Calvetti ◽

Seegar Swanson ◽

...

Keyword(s):

Clinical Trials ◽

Optic Neuritis ◽

Randomized Clinical Trials ◽

Mail Survey ◽

Standard Of Care ◽

High Dose ◽

Acute Optic Neuritis ◽

Disease Modifying ◽

Disease Modifying Agents ◽

The Impact

ABSTRACTBackground:Acute isolated optic neuritis is often the first manifestation of multiple sclerosis (MS), and its management remains controversial. Over the past decade, with the advent of new disease-modifying agents, management of isolated optic neuritis has become more complicated.Objectives:To evaluate the current practice patterns of Canadian ophthalmologists and neurologists in the management of acute optic neuritis, and to evaluate the impact of recently published randomized clinical trials.Design:Mail survey.Methods:All practicing ophthalmologists and neurologists in Canada were mailed a survey evaluating the management of isolated acute optic neuritis and familiarity with recent clinical trials. Surveys for 1158 were mailed, and completed surveys were collected anonymously through a datafax system. Second and third mailings were sent to non-respondents 6 and 12 weeks later.Results:The final response rate was 34.5%. Although many acute optic neuritis patients initially present to ophthalmologists, neurologists are the physicians primarily managing these patients. Ordering magnetic resonance imaging, and treating with high dose intravenous steroids has become the standard of care. However, 15% of physicians (14% of ophthalmologists and 16% of neurologists) continue to prescribe low dose oral steroids, and steroids are being given for reasons other than to shorten the duration of visual symptoms by 73% of ophthalmologists and 50% of neurologists. More neurologists than ophthalmologists are familiar with recent clinical trials involving disease-modifying agents.Conclusion:Although the management of acute optic neuritis has been evaluated in large clinical trials that were published in major international journals, some ophthalmologists and neurologists are not following evidence-based recommendations.

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Dose dependent evolutionary game dynamics modulate competitive release in cancer therapy

10.1101/2020.09.18.303966 ◽

2020 ◽

Author(s):

Nathan Farrokhian ◽

Jeff Maltas ◽

Patrick Ellsworth ◽

Arda Durmaz ◽

Mina Dinh ◽

...

Keyword(s):

Clinical Trials ◽

Growth Models ◽

Evolutionary Game ◽

Treatment Strategies ◽

Tumor Control ◽

Initial Population ◽

Game Dynamics ◽

Competitive Release ◽

The Impact

ABSTRACTTherapeutic strategies for tumor control have traditionally assumed that maximizing reduction in tumor volume correlates with clinical efficacy. Unfortunately, this rapid decrease in tumor burden is almost invariably followed by the emergence of therapeutic resistance. Evolutionary based treatment strategies work to delay this inevitability by promoting the maintenance of tumoral heterogeneity. While these strategies have shown promise in recent clinical trials, they often rely on biological conjecture and intuition to derive parameters. Reproducibility of the success seen with this treatment paradigm is contingent on formal elucidation of underlying subclonal interactions. One such consequence of these interactions, “competitive release”, is an evolutionary phenomenon that describes the unopposed proliferation of resistant populations following maximally tolerated systemic therapies. While often assumed in evolutionary models of cancer, here we show the first empiric evidence of “competitive release” occurring in an in vitro tumor environment. We found that this phenomenon is modulated by both drug dose and initial population composition. As such, we observed that monotypic fitness differentials were insufficient to accurately predict the outcomes of this phenomenon. Instead, derivation of underlying frequency dependent evolutionary game dynamics is essential to understand resulting sub-population shifts through time. To evaluate the impact of these non-autonomous growth behaviors over longer time series, we used a range of commonly employed growth models, some of which are the foundation of ongoing clinical trials. While useful for identifying persistent qualitative features, we observed significant fragility and model specific behaviors that limited the ability of these models to make consistent quantitative predictions, even when the parameters were empirically derived.

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Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009870 ◽

2021 ◽

Vol 15 (10) ◽

pp. e0009870

Author(s):

Nina Svensen ◽

Susan Wyllie ◽

David W. Gray ◽

Manu De Rycker

Keyword(s):

Clinical Trials ◽

Chagas Disease ◽

Time Resolution ◽

Standard Of Care ◽

Live Imaging ◽

Model Systems ◽

High Time Resolution ◽

Laboratory Findings

Chagas disease, caused by the protozoan intracellular parasite Trypanosoma cruzi, is a highly neglected tropical disease, causing significant morbidity and mortality in central and south America. Current treatments are inadequate, and recent clinical trials of drugs inhibiting CYP51 have failed, exposing a lack of understanding of how to translate laboratory findings to the clinic. Following these failures many new model systems have been developed, both in vitro and in vivo, that provide improved understanding of the causes for clinical trial failures. Amongst these are in vitro rate-of-kill (RoK) assays that reveal how fast compounds kill intracellular parasites. Such assays have shown clear distinctions between the compounds that failed in clinical trials and the standard of care. However, the published RoK assays have some key drawbacks, including low time-resolution and inability to track the same cell population over time. Here, we present a new, live-imaging RoK assay for intracellular T. cruzi that overcomes these issues. We show that the assay is highly reproducible and report high time-resolution RoK data for key clinical compounds as well as new chemical entities. The data generated by this assay allow fast acting compounds to be prioritised for progression, the fate of individual parasites to be tracked, shifts of mode-of-action within series to be monitored, better PKPD modelling and selection of suitable partners for combination therapy.

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Impact of mTOR Inhibition on FoxP3+ Regulatory T Cells as Compared to Conventional T Cells after Allogeneic Bone Marrow Transplantation.

Blood ◽

10.1182/blood.v108.11.448.448 ◽

2006 ◽

Vol 108 (11) ◽

pp. 448-448 ◽

Cited By ~ 1

Author(s):

Robert Zeiser ◽

Dennis B. Leveson-Gower ◽

Elizabeth A. Zambricki ◽

Jing-Zhou Hou ◽

Robert Negrin

Keyword(s):

Clinical Trials ◽

T Cells ◽

Regulatory T Cells ◽

Allogeneic Bone Marrow Transplantation ◽

Inhibitory Effect ◽

Allogeneic Bone ◽

Mtor Inhibition ◽

The Impact

Abstract FoxP3+CD4+CD25+ regulatory T-cells (Treg) have been shown to effectively reduce the severity of experimental acute graft-versus-host disease (aGvHD) while sparing graft-versus-leukemia activity. These findings, in concert with the observation that human and murine Treg share functional characteristics, have fueled interest in clinical trials to control aGvHD. Recent data indicates that the immunosuppressant rapamycin (RAPA) in contrast to cyclosporine A does not interfere with in vivo function of Treg and could enhance Treg expansion in vitro by a yet unknown mechanism. To investigate the impact of mTOR inhibition on proliferating Treg and Tconv, both cell types were exposed to CD3/CD28 Mabs in the presence of different RAPA concentrations in vitro. Phosphorylation of mTOR downstream products p70S6K1 and 4E-BP1 were assessed by western blot and flow cytometry. Inhibition of the phosphorylation of p70S6K1 and 4E-BP1 was observed in both populations in the presence of RAPA. Interestingly, Treg were more resistant to mTOR inhibition as compared to Tconv and displayed significantly higher phosphorylated products in the presence of RAPA at 10 nM (MFI Treg vs Tconv, p<0.001) and at 100nM (MFI Treg vs Tconv, p<0.001). To investigate whether Treg and RAPA protect from aGvHD in a synergistic manner, BALB/c recipients were transplanted with H-2 disparate BM and 1.6x10e6 T-cells (FVB/N) after lethal irradiation (8 Gy). aGvHD lethality was only slightly reduced when suboptimal Tconv:Treg ratios were employed (4:1, 8:1), or when recipients were treated with a non-protective RAPA dose (0.5 mg/kg bodyweight). Combining a suboptimal Tconv:Treg ratio with a non-protective RAPA dose reduced expansion of luciferase expressing (luc+) Tconv and pro-inflamatory cytokines and improved survival indicative for an additive in vivo effect of RAPA and Treg. To evaluate the impact of RAPA on in vivo T cell expansion, either luc+ Tconv or luc+ Treg were adoptively transferred. In vivo bioluminescence imaging demonstrated that RAPA had a more potent inhibitory effect on proliferation of Tconv as compared to Treg (p<0.05 vs. NS). We did not observe RAPA to increase FoxP3+ Treg numbers in vivo, or to enhance GITR or CTLA-4 expression. Thus, increased Treg numbers observed in RAPA containing expansion cultures are likely due to a lower susceptibility of this cell population to mTOR inhibition. This could explain the observed synergistic effect of RAPA and Treg in aGvHD protection which has relevance for clinical trials utilizing Treg to prevent aGvHD.

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