Mathematical modelling of malaria chemotherapy: combining artesunate and mefloquine

Clinical data on the use of artesunate combined with mefloquine in a variety of treatment regimens and parasite loads in Thailand were modelled on the basis of experimentally determined pharmacokinetic data. The model assumed no pharmacodynamic interaction between artesunate and mefloquine, but that the parasites were already resistant to mefloquine. Predictions of the model accorded well with the data. In particular, in accordance with clinical observations, the model showed that monotherapy with either drug failed to cure at moderate parasitaemia, yet such patients could be treated effectively with the combination of 3 days of artesunate + mefloquine. For high levels of parasitaemia, 5 days of artesunate+mefloquine were needed. Simulations were also performed for situations of lower resistance to mefloquine and for the immune human populations found in Africa. The importance of mathematical modelling of combination therapy is borne out by this study and suggests its wider application for other drug combinations.

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A systematic review and meta-analysis protocol examining the clinical characteristics and epidemiological features of olfactory dysfunction (OD) in coronavirus disease 2019 (COVID-19)

Systematic Reviews ◽

10.1186/s13643-021-01624-6 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Rosemond Qian-Xiu Tan ◽

Wai Tak Victor Li ◽

Wing-Zi Shum ◽

Sheung Chit Chu ◽

Hang-Long Li ◽

...

Keyword(s):

Systematic Review ◽

Clinical Data ◽

Systematic Reviews ◽

Clinical Characteristics ◽

Meta Analysis ◽

Olfactory Dysfunction ◽

Statistical Analyses ◽

Human Populations ◽

Meta Analyses ◽

Analysis Protocol

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has caused recurring and major outbreaks in multiple human populations around the world. The plethora of clinical presentations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been described extensively, of which olfactory dysfunction (OD) was established as an important and common extrapulmonary manifestation of COVID-19 infection. The aim of this protocol is to conduct a systematic review and meta-analysis on peer-reviewed articles which described clinical data of OD in COVID-19 patients. Methods This research protocol has been prospectively registered with the Prospective Register of Systematic Reviews (PROSPERO; CRD42020196202). CINAHL, ClinicalTrials.gov, Cochrane Central, EMBASE, MEDLINE and PubMed, as well as Chinese medical databases China National Knowledge Infrastructure (CNKI), VIP and WANFANG, will be searched using keywords including ‘COVID-19’, ‘coronavirus disease’, ‘2019-nCoV’, ‘SARS-CoV-2’, ‘novel coronavirus’, ‘anosmia’, ‘hyposmia’, ‘loss of smell’, and ‘olfactory dysfunction’. Systematic review and meta-analysis will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Articles will be screened according to pre-specified inclusion and exclusion criteria to extract studies that include new clinical data investigating the effect of COVID-19 on olfactory dysfunction. Included articles will be reviewed in full; data including patient demographics, clinical characteristics of COVID-19-related OD, methods of olfactory assessment and relevant clinical outcomes will be extracted. Statistical analyses will be performed using the Comprehensive Meta-Analysis version 3. Discussion This systematic review and meta-analysis protocol will aim to collate and synthesise all available clinical evidence regarding COVID-19-related OD as an important neurosensory dysfunction of COVID-19 infection. A comprehensive search strategy and screening process will be conducted to incorporate broad clinical data for robust statistical analyses and representation. The outcome of the systematic review and meta-analysis will aim to improve our understanding of the symptomatology and clinical characteristics of COVID-19-related OD and identify knowledge gaps in its disease process, which will guide future research in this specific neurosensory defect. Systematic review registration PROSPERO registration number: CRD42020196202.

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The IDentif.AI 2.0 Pandemic Readiness Platform: Rapid Prioritization of Optimized COVID-19 Combination Therapy Regimens

10.1101/2021.06.23.21259321 ◽

2021 ◽

Author(s):

Agata Blasiak ◽

Anh TL Truong ◽

Alexandria Remus ◽

Lissa Hooi ◽

Shirley Gek Kheng Seah ◽

...

Keyword(s):

Combination Therapy ◽

Drug Efficacy ◽

Drug Combinations ◽

Multiple Drug ◽

Original Strain ◽

Live Virus ◽

Drug Synergy ◽

Positive Treatment ◽

Strong Candidate ◽

Combination Regimens

Objectives: We aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19. Methods: A pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain and B.1.351 variant) and Vero E6 assay with a quadratic optimization workflow. Results: Within 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived. Conclusions: IDentif.AI 2.0 rapidly revealed promising drug combinations for a clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence.

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Combination therapy with amisulpride and antidepressants: Clinical observations in case series of elderly patients with psychotic depression

Progress in Neuro-Psychopharmacology and Biological Psychiatry ◽

10.1016/j.pnpbp.2008.03.011 ◽

2008 ◽

Vol 32 (5) ◽

pp. 1227-1230 ◽

Cited By ~ 5

Author(s):

Antonis M. Politis ◽

George N. Papadimitriou ◽

Christos G. Theleritis ◽

Constantin Psarros ◽

Constantin R. Soldatos

Keyword(s):

Combination Therapy ◽

Elderly Patients ◽

Case Series ◽

Psychotic Depression ◽

Clinical Observations

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Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1346 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1346-1351 ◽

Cited By ~ 26

Author(s):

C A Deminie ◽

C M Bechtold ◽

D Stock ◽

M Alam ◽

F Djang ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Combination Therapy ◽

Protease Inhibitor ◽

Reverse Transcriptase ◽

Protease Inhibitors ◽

Nucleoside Analogs ◽

Drug Combinations ◽

Hiv Protease ◽

Human Immunodeficiency Virus Replication ◽

Immunodeficiency Virus

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.

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P805 Clinical and echocardiographic characteristics of Polish patients with Eisenmenger Syndrome - results of a snapshot registry

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez319.461 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

Author(s):

A Mamzer-Dachnowska ◽

G Kopec ◽

B Kusmierczyk ◽

W Skowron ◽

E Mroczek ◽

...

Keyword(s):

Heart Disease ◽

Combination Therapy ◽

Clinical Data ◽

National Registry ◽

Current Therapy ◽

Eisenmenger Syndrome ◽

Duration Of Treatment ◽

Multicenter Observational Study ◽

Heart Defect ◽

Annual Mortality

Abstract The first national registry of patients (pts) with PAH-CHD, predominantly with Eisenmenger Syndrome (ES), treated within national program was conducted. We studied clinical and echocardiographic characteristics of a group of adult patients including current therapy profile and mortality. A multicenter observational study (snapshot registry) was conducted under auspices of Polish Cardiac Society, including pts with PAH-CHD, identified in centers, that treated > 5 pts in the first 10 years of therapeutic program (2008-2018). This analysis included 322 pts (70 deceased), mean age 42 ± 2 years, 65% females. The registry included patients meeting the criteria of the Eisenmenger syndrome in echocardiography (right-left or aligned leak). The living patients were divided into 2 groups: Gr.1 (n = 227) – uncorrected and Gr.2 (n = 25) - after correction of the heart disease. The average age in Gr.1 was 40 ± 2 years, in Gr.2 40 ± 6 years. The majority were women (68% and 62%). There was no significant differences for mean duration of treatment in groups: 60 ± 12 months vs. 66 ± 6 months (p = 0.42). Both groups didn’t differ in terms of clinical data, i.e. 6MWT 417 ± 50 m vs. 384 ± 15 m;p = 0.15, NT-proBNP level 869 ± 470 pg/ml vs. 901 ± 212 pg/ml;p = 0.57. There was no significant differences for mean LVd in groups: 41,24 mm [12-82] vs. 44,25 mm [30-55]. Mean LVEF was good (60% in gr.1 vs. 57% in gr.2). Mean TAPSE was slightly better in Gr.1: 19,36 mm vs. 17,09 mm. Pericardial effusion were present in almost 15% pts from Gr.1 and less than 1% pts from Gr.2. Pts after correction were mostly in the II WHO FC, and those uncorrected in the II/III WHO FC. Pts from Gr.2 were more likely to receive polytherapy (60% vs. 47%). ERA were the most commonly used (near 90%). The most common heart defect was VSD (46% in Gr.1 vs. 32% in Gr.2). Mortality was 22% in entire period, i.e. annual mortality rate of 2.2%. In the group of dead pts women accounted for 74%, the average age was 49 ± 4 years and mean length of treatment was 42 ± 13 months. About 9% of pts from this group had heart defect correction in the past. Monotherapy (66%) predominated among the deceased, mainly using ERA (77%). Pts receiving combination therapy had a longer survival (p = 0.04). It isn’t known whether this result confirms the greater effectiveness of such treatment, as some patients couldn’t wait until the polytherapy became possible within the framework of the Drug Program. Among the deceased, the most common heart disease was ASD (30%), slightly less VSD (29%). In this first national snapshot registry we documented improving prognosis in PAH-CHD under specific therapies. No differences were present in the length of therapy, clinical data and quality of life depending on whether or not correction surgery was performed. Post-correction pts more often received a polytherapy. The annual mortality in this population is small estimated just over 2%. Targeted combination therapy may contribute to better survival.

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Abstract 5147: drugCARD: a database of anticancer treatment regimens and drug combinations.

10.1158/1538-7445.am2013-5147 ◽

2013 ◽

Cited By ~ 2

Author(s):

Eric Fernandez ◽

Jianxiong Pang ◽

Chris Snell ◽

Cathy Derow ◽

Frances Brightman ◽

...

Keyword(s):

Drug Combinations ◽

Treatment Regimens ◽

Anticancer Treatment

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Use of a modified Delphi panel to define value of combination therapy in oncology.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18369 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18369-e18369

Author(s):

Michael Broder ◽

Harshali Patel ◽

Zac Wessler ◽

Sarah Gibbs ◽

Irina Yermilov ◽

...

Keyword(s):

Combination Therapy ◽

Health Outcomes ◽

Cultural Beliefs ◽

Unmet Need ◽

Delphi Panel ◽

Combination Therapies ◽

Cancer Treatments ◽

Treatment Regimens ◽

Modified Delphi ◽

Tumor Types

e18369 Background: Treatment regimens involving 2+ novel oncologics have improved health outcomes in several tumor types. These regimens have significantly higher costs than single agents and older treatments (e.g., chemotherapies), which are still widely used to treat different cancers. Our goal was to determine if current concepts of “value,” such as those described by ICER and other frameworks, adequately capture the value of combination therapies. Methods: Using a RAND/UCLA modified Delphi panel, 8 experts from various backgrounds were provided with a review of current concepts of value and asked to rate them on measurability, relevance, and necessity to determine a combination therapy’s value from 4 perspectives (patient, physician, payer, society). After the first round of ratings, panelists met in person and discussed areas of disagreement. Ratings were repeated, and results used to quantitatively summarize group opinion on concepts recommended for inclusion in a value definition. Results: In both rating rounds, experts agreed treatment, clinical evidence, and health outcomes as important domains in determining value. Experts disagreed on whether societal/cultural beliefs, disease factors (i.e., rarity of cancer, unmet need, burden of disease), and other elements of value (e.g., insurance value, reduction in uncertainty, treatment affordability) needed to be incorporated into value assessments of combinations. Responses differed by perspective. Concepts on which there was disagreement decreased post-meeting (23% to 9%). Conclusions: Experts agreed that “value” for 2+ novel oncologics would have a similar definition to value for all high cost oncology therapies. Four key research opportunities to characterize the value of combination therapy emerged: societal context and patient preference may affect value assessments but are not widely considered in current models; some important benefits are not recognized by patients and may be missed by traditional value assessments; given typical patient and societal preferences, cancer treatments may be systematically undervalued vis a vis other health conditions; and combination therapies may present challenges for recently promulgated value frameworks.

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