Host-directed therapies for infectious diseases: current status, recent progress, and future prospects

Zumla, Alimuddin; Rao, Martin; Wallis, Robert S.; Kaufmann, Stefan H. E.; Rustomjee, Roxana; Mwaba, Peter; Vilaplana, Cristina; Yeboah-Manu, Dorothy; Chakaya, Jeremiah; Ippolito, Giuseppe; Azhar, Esam I.; Höelscher, Michael; Maeurer, Markus

doi:10.1016/s1473-3099(16)00078-5

Cited by 270 publications

(230 citation statements)

References 171 publications

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“…ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1)(2)(3)(4)(5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6).…”

mentioning

confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the firstline regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.KEYWORDS Mycobacterium tuberculosis, metformin, standard first-line regimen, BALB/c, bactericidal, sterilizing, host-directed therapy, relapse, cure, Denver regimen H ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1-5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6). In another retrospective study, Srujitha et al. showed that MetF use was associated with a 3.9-fold reduction in TB incidence among patients with DM (7). Based on these findings, we hypothesized that MetF adjunctive therapy would enhance the bactericidal and sterilizing activities of the standard first-line treatment (8, 9) against chronic TB infection in mice and shorten the duration of curative treatment as assessed by microbiological relapse.All animal-related procedures were approved by the Johns Hopkins University (JHU) School of Medicine Animal Care and Use Committee. A total of 170 female BALB/c mice aged 4 to 6 weeks (Charles River Labs, Wilmington, MA) were aerosol infected with Mycobacterium tuberculosis H37Rv (JHU) using the inhalation exposure system (GlasCol, Terre Haute, IN) calibrated to deliver ϳ10 2 CFU per mouse lung in two consecutive runs. After aerosol infection, the mice were randomized into the two treatment groups. Six weeks postinfection, the mice were treated daily (5 days/week) via esophageal cannulation with human-equivalent doses of rifampin (10 mg/kg), isoniazid (10 mg/kg), pyrazinamide (150 mg/kg), and ethambutol (100 mg/kg) (RHZE) with or without MetF (250 mg/kg) for up to 6 months (2, 10, 11). For the first 2 months of treatment, the mice received RHZE and, for the remaining 4 months, only rifampin and isoniazid (RH) to mirror the first-line regimen in humans. The rifampin dose preceded that of the other drugs by at least 1 h to prevent pharmacokinetic antagonism (12, 13). The dose of MetF (6) and is estimated (14) to be equivalent to 25 mg/kg in humans (15), which is well tolerated (15, 16). Groups of 5 mice were sacrificed on the day after infection, on the day of treatment initi...

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confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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“…[1][2][3] Since the first Food and Drug Administration (FDA)-approved TMA in 1986, the market of TMAs has grown exponentially, with approximately 50 antibodies approved and over 70 expected in 2020. 4 Among them, TMAs targeting the tyrosine kinase receptors that are overexpressed in several tumor cell subsets (eg, trastuzumab [TZ; Trastuzumab-Herceptinhave initiated a new paradigm for targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

“…We demonstrated that either the released antibodies or the nanocomplexes are able to exert an effective antitumor activity in HER2-positive breast cancer cells both by direct action on cell signaling transduction and by cell-mediated cytotoxicity. ) was supplied by Pfizer, NY, USA, and used after HCl removal by incubation with three molar excess of trimethylamine in CHCl 3 . TZ (Herceptin ® ) was supplied by Genentech (South San Francisco, CA, USA).…”

Section: Introductionmentioning

confidence: 99%

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Colzani¹,

Pandolfi²,

Hoti³

et al. 2018

IJN

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Background We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic- co -glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Materials and methods Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. Results and discussion TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. Conclusion With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy.

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“…The ALM therapy has a number of potential advantages for clinical adoption, as follows: (i) the drug combination is used at higher concentrations as a "polarizing" cardioplegia in cardiac surgery, and a recent prospective randomized trials showed its superiority over the standard of care (49); (ii) early drug infusion time for infection control is short (4 h); (iii) the small volume avoids the untoward pulmonary and cardiac problems of colloidal or larger-volume saline-based fluid therapies (37); and (iv) the therapy may help to bolster the host's early response to fight other "stressors," i.e., viral or parasitic infections (24), including buying biological time for victims of Ebola and other viral hemorrhagic diseases.…”

Section: Figmentioning

confidence: 99%

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

Griffin

Letson

Dobson

2016

Clin Vaccine Immunol

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Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of a small-volume 0.9% NaCl adenosine, lidocaine, and Mg 2؉ (ALM) bolus and a 4-h intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to that of controls (25%). Four controls died on day 2 to 3, and two died on day 5. Early death was associated with elevated plasma and lung inflammatory markers (interleukin-6 [IL-6], IL-1␤, C-reactive protein), reduced white blood cell (WBC) count, hypoxemia, hypercapnia, acidosis, hyperkalemia, and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil-dominated WBC rebound/overshoot, increased lung oxidant injury, edema, and persistent ischemia. On day 6, seven of eight ALM survivors had inflammatory and immunological profiles not significantly different from those of sham-treated animals. We conclude in the rat model of experimental sepsis that small-volume ALM treatment led to higher survivability at 6 days (88%) than that of controls (25%). Early death in controls (day 2 to 3) was associated with significantly elevated plasma levels of IL-1␤, IL-6, and C-reactive protein, severe plasma lymphocyte deficiency, reduced neutrophils, and acute lung injury. Late death (day 5) was associated with a massive neutrophil inflammatory storm, increased lung injury, and persistent ischemia. Possible mechanisms of ALM protection are discussed. G lobally, 1,000 people die from sepsis every hour, claiming more lives than trauma, heart attack, or cancer (1-3). Sepsis develops from the host's response to an infection involving an overexpression of systemic inflammation, coagulopathy, immune dysfunction, and eventually multiple-organ failure (4,5). Over the past 2 decades, despite new antimicrobial/antifungal agents and advanced life support systems, the case fatality rate for patients with sepsis has remained at 20% to 30% and up to 50% in lowincome countries (3,4,6). An ongoing concern is why do some patients who receive state-of-the-art treatment die and others live? The reasons are complex but appear to be related to the type and unpredictable nature of pathogen progression (2, 5, 7), the degree of autonomic and cardiac dysfunction that develops (8), and the lack of a suitable frontline drug therapy to protect against the inability of the immune system to discriminate self from non-self, causing widespread tissue injury and eventually death.Previously, we have shown in the rat model of polymicrobial sepsis, induced by cecal ligation and puncture (CLP), that smallvolume adenosine, lidocaine, and Mg 2ϩ (ALM) induced a stable, hypotensive state over 5 h with no arrhythmias, significantly less pulmonary edema, and corrected coagulopathy (9). The ALM concept has also translated to the pig model of lipopolysaccharide endotoxemia (10). In comparison to controls, ALM infusion led to a mild hibernation-like state that decreased mean arterial pres...

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Host-directed therapies for infectious diseases: current status, recent progress, and future prospects

Cited by 270 publications

References 171 publications

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

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Host-directed therapies for infectious diseases: current status, recent progress, and future prospects

Cited by 270 publications

References 171 publications

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Small-Volume Adenosine, Lidocaine, and Mg 2+ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics

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Small-Volume Adenosine, Lidocaine, and Mg ²⁺ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics