Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery—A Comprehensive Review of the Literature

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with an extremely poor prognosis. There is a dire need to develop effective therapeutics to overcome the intrinsic and acquired resistance of GBM to current therapies. The process of developing novel anti-neoplastic drugs from bench to bedside can incur significant time and cost implications. Drug repurposing may help overcome that obstacle. A wide range of drugs that are already approved for clinical use for the treatment of other diseases have been found to target GBM-associated signaling pathways and are being repurposed for the treatment of GBM. While many of these drugs are undergoing pre-clinical testing, others are in the clinical trial phase. Since GBM stem cells (GSCs) have been found to be a main source of tumor recurrence after surgery, recent studies have also investigated whether repurposed drugs that target these pathways can be used to counteract tumor recurrence. While several repurposed drugs have shown significant efficacy against GBM cell lines, the blood–brain barrier (BBB) can limit the ability of many of these drugs to reach intratumoral therapeutic concentrations. Localized intracranial delivery may help to achieve therapeutic drug concentration at the site of tumor resection while simultaneously minimizing toxicity and side effects. These strategies can be considered while repurposing drugs for GBM.

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Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

Current Medicinal Chemistry ◽

10.2174/0929867324666171023163752 ◽

2019 ◽

Vol 26 (23) ◽

pp. 4323-4354 ◽

Cited By ~ 9

Author(s):

Ana Cristina Lima Leite ◽

José Wanderlan Pontes Espíndola ◽

Marcos Veríssimo de Oliveira Cardoso ◽

Gevanio Bezerra de Oliveira Filho

Keyword(s):

Biologically Active ◽

Neglected Diseases ◽

Financial Return ◽

Drug Candidates ◽

Lead Compounds ◽

Wide Range ◽

Methods Of Synthesis ◽

Current Therapies ◽

Resistant Strains ◽

Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

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Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽

10.3390/molecules26020278 ◽

2021 ◽

Vol 26 (2) ◽

pp. 278

Author(s):

Jennifer Lagoutte-Renosi ◽

Bernard Royer ◽

Vahideh Rabani ◽

Siamak Davani

Keyword(s):

Active Metabolite ◽

Plasma Concentrations ◽

Antiplatelet Agent ◽

High Plasma ◽

Therapeutic Drug ◽

Routine Practice ◽

Daily Routine ◽

Limit Of Quantification ◽

Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

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Software for Dosage Individualization of Voriconazole for Immunocompromised Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02025-12 ◽

2013 ◽

Vol 57 (4) ◽

pp. 1888-1894 ◽

Cited By ~ 28

Author(s):

William W. Hope ◽

Michael VanGuilder ◽

J. Peter Donnelly ◽

Nicole M. A. Blijlevens ◽

Roger J. M. Brüggemann ◽

...

Keyword(s):

Therapeutic Drug Monitoring ◽

Drug Monitoring ◽

Fungal Infections ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Cell Transplant ◽

Multiple Model ◽

Pharmacokinetic Variability ◽

Hematopoietic Stem ◽

Wide Range

ABSTRACTThe efficacy of voriconazole is potentially compromised by considerable pharmacokinetic variability. There are increasing insights into voriconazole concentrations that are safe and effective for treatment of invasive fungal infections. Therapeutic drug monitoring is increasingly advocated. Software to aid in the individualization of dosing would be an extremely useful clinical tool. We developed software to enable the individualization of voriconazole dosing to attain predefined serum concentration targets. The process of individualized voriconazole therapy was based on concepts of Bayesian stochastic adaptive control. Multiple-model dosage design with feedback control was used to calculate dosages that achieved desired concentration targets with maximum precision. The performance of the software program was assessed using the data from 10 recipients of an allogeneic hematopoietic stem cell transplant (HSCT) receiving intravenous (i.v.) voriconazole. The program was able to model the plasma concentrations with a high level of precision, despite the wide range of concentration trajectories and interindividual pharmacokinetic variability. The voriconazole concentrations predicted after the last dosages were largely concordant with those actually measured. Simulations provided an illustration of the way in which the software can be used to adjust dosages of patients falling outside desired concentration targets. This software appears to be an extremely useful tool to further optimize voriconazole therapy and aid in therapeutic drug monitoring. Further prospective studies are now required to define the utility of the controller in daily clinical practice.

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Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22126569 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6569

Author(s):

Christoph Roderburg ◽

Sven H. Loosen ◽

Jan Bednarsch ◽

Patrick H. Alizai ◽

Anjali A. Roeth ◽

...

Keyword(s):

Tumor Recurrence ◽

Tumor Biology ◽

Tumor Resection ◽

Postoperative Outcome ◽

Serum Levels ◽

Strong Trend ◽

Programmed Cell Death 1 ◽

Early Tumor ◽

Circulating Levels

Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients’ prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC. Methods: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls. Results: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome. Conclusion: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome.

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Iodine-125 interstitial brachytherapy after tumor excision: an alternative eye-sparing surgery for lacrimal gland carcinoma

10.21203/rs.3.rs-154192/v1 ◽

2021 ◽

Author(s):

Yang-jun Li ◽

Ping Wang ◽

Shao-bo Zhang ◽

Xiao-na Ning ◽

Chen-jun Guo ◽

...

Keyword(s):

Lacrimal Gland ◽

Tumor Recurrence ◽

Tumor Resection ◽

Interstitial Brachytherapy ◽

Tumor Excision ◽

Control Tumor ◽

Gland Carcinoma ◽

Iodine 125 ◽

Good Cosmesis

Abstract Background:To describe the preliminary suppressive effects of iodine 125 brachytherapy for malignant lacrimal gland tumors after excisionMethods:The study recruit 9 patients with lacrimal gland carcinoma from May 2017 to December 2020. All patients underwent eye sparing surgical tumor resection first and then received iodine 125 interstitial brachytherapy to prevent tumor recurrence. We look over whether tumor recurred or metastasized by detecting the visual function and CT/MRI/PET MRI of every patient.Results1 patient was lost visit. The median follow up period was 29 months of other 8 patients (range, 7 43 months). One patient experienced recurrence two years later but was free from local disease after iodine 125 seeds were implanted one more time. The vision of one female patient was lost due to the seeds moving to the optic nerve. In the remaining 6 patients the vision was no changed, and CT/MRI showed no tumor was recurrencedConclusions:Permanent iodine 125 strip implantation in the orbit can be used as an alternative eye sparing surgery for malignant lacrimal gland tumors after tumor excision. It can control tumor recurrence and maintenance of vision and good cosmesis.

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Exosome-Mediated Insulin Delivery for the Potential Treatment of Diabetes Mellitus

Pharmaceutics ◽

10.3390/pharmaceutics13111870 ◽

2021 ◽

Vol 13 (11) ◽

pp. 1870

Author(s):

Belén Rodríguez-Morales ◽

Marilena Antunes-Ricardo ◽

José González-Valdez

Keyword(s):

Diabetes Mellitus ◽

Human Insulin ◽

Insulin Delivery ◽

Dermal Fibroblasts ◽

Therapeutic Drug ◽

Extracellular Medium ◽

Glucose Levels ◽

Wide Range ◽

Diabetes Mellitus Treatment

Exosomes are extracellular nanovesicles between 30 and 150 nm that serve as essential messengers for different biological signaling and pathological processes. After their discovery, a wide range of applications have been developed, especially in therapeutic drug delivery. In this context, the aim of this work was to test the efficiency of exosome-mediated human insulin delivery using exosomes extracted from three different cell lines: hepatocellular carcinoma (HepG2); primary dermal fibroblasts (HDFa) and pancreatic β cells (RIN-m); all are related to the production and/or the ability to sense insulin and to consequently regulate glucose levels in the extracellular medium. The obtained results revealed that the optimal insulin loading efficiency was achieved by a 200 V electroporation, in comparison with incubation at room temperature. Moreover, the maximum in vitro exosome uptake was reached after incubation for 6 h, which slightly decreased 24 h after adding the exosomes. Glucose quantification assays revealed that exosome-mediated incorporation of insulin presented significant differences in HDFa and HepG2 cells, enhancing the transport in HDFa, in comparison with free human insulin effects in the regulation of extracellular glucose levels. No significant differences were found between the treatments in RIN-m cells. Hence, the results suggest that exosomes could potentially become a valuable tool for stable and biocompatible insulin delivery in diabetes mellitus treatment alternatives.

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Translational and Clinical Pharmacology Considerations in Drug Repurposing for X-linked Adrenoleukodystrophy-A Rare Peroxisomal Disorder

10.22541/au.162610374.45880274/v1 ◽

2021 ◽

Author(s):

Julianne Tieu ◽

Siddhee Sahasrabudhe ◽

Paul Orchard ◽

James Cloyd ◽

Reena Kartha

Keyword(s):

Drug Target ◽

Drug Targets ◽

Drug Repurposing ◽

Pharmacokinetics And Pharmacodynamics ◽

Drug Candidates ◽

Target Patient Population ◽

Site Of Action ◽

Repurposed Drugs ◽

Gait Disturbances ◽

Spastic Quadriparesis

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

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Fibrotic expression profile analysis reveals repurposed drugs with potential anti-fibrotic mode of action

PLoS ONE ◽

10.1371/journal.pone.0249687 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249687

Author(s):

Evangelos Karatzas ◽

Andrea C. Kakouri ◽

George Kolios ◽

Alex Delis ◽

George M. Spyrou

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Profile Analysis ◽

Oral Submucous Fibrosis ◽

Drug Repurposing ◽

Biological Pathways ◽

Igg4 Related Disease ◽

Submucous Fibrosis ◽

Repurposed Drugs ◽

Fibrotic Diseases

Fibrotic diseases cover a spectrum of systemic and organ-specific maladies that affect a large portion of the population, currently without cure. The shared characteristic these diseases feature is their uncontrollable fibrogenesis deemed responsible for the accumulated damage in the susceptible tissues. Idiopathic Pulmonary Fibrosis, an interstitial lung disease, is one of the most common and studied fibrotic diseases and still remains an active research target. In this study we highlight unique and common (i) genes, (ii) biological pathways and (iii) candidate repurposed drugs among 9 fibrotic diseases. We identify 7 biological pathways involved in all 9 fibrotic diseases as well as pathways unique to some of these diseases. Based on our Drug Repurposing results, we suggest captopril and ibuprofen that both appear to slow the progression of fibrotic diseases according to existing bibliography. We also recommend nafcillin and memantine, which haven’t been studied against fibrosis yet, for further wet-lab experimentation. We also observe a group of cardiomyopathy-related pathways that are exclusively highlighted for Oral Submucous Fibrosis. We suggest digoxin to be tested against Oral Submucous Fibrosis, since we observe cardiomyopathy-related pathways implicated in Oral Submucous Fibrosis and there is bibliographic evidence that digoxin may potentially clear myocardial fibrosis. Finally, we establish that Idiopathic Pulmonary Fibrosis shares several involved genes, biological pathways and candidate inhibiting-drugs with Dupuytren’s Disease, IgG4-related Disease, Systemic Sclerosis and Cystic Fibrosis. We propose that treatments for these fibrotic diseases should be jointly pursued.

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Multiple cystic lesions in the abdominopelvic cavity one and a half years after resection of presacral neurogenic tumor: tumor recurrence or other?

International Surgery Journal ◽

10.18203/2349-2902.isj20205379 ◽

2020 ◽

Vol 7 (12) ◽

pp. 4180

Author(s):

Umar Zeb Khan ◽

Matiullah Masroor ◽

Hai Liu

Keyword(s):

Spontaneous Rupture ◽

Tumor Recurrence ◽

Tumor Resection ◽

Abdominal Distension ◽

Neurogenic Tumor ◽

Ct Scans ◽

Cystic Degeneration ◽

Cystic Lesions ◽

Local Hospital ◽

Neurogenic Tumors

Cystic lesions of abdominopelvic cavity include a variety of pathologies and diagnosis can sometimes be challenging. Urinoma can be caused by iatrogenic injury, spontaneous rupture of ureters or by various causes of ureteral obstruction. It needs to be differentiated from abdominopelvic cystic diseases including tumors that can undergo cystic degeneration. Here we report a case of a 41 years old female underwent a presacral neurogenic tumor resection at a local hospital 5 years ago. The tumor recurred three and a half years after the first surgery and removed at another hospital. She experienced abdominal distension and difficulty in urination from the last 2 months and was diagnosed as having a recurrence of tumor once again at both hospitals on separate CT scans. They believed that the tumor was too large and encroaching on adjacent organs to be surgically resected, she was finally diagnosed as infected urinoma during surgery in our hospital. Even though spontaneous rupture of ureters and urinoma formation is a rare disease but it should be considered as a main differential diagnosis of recurrence of neurogenic tumors especially in post abdominopelvic surgeries patient.

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Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00756-15 ◽

2015 ◽

Vol 59 (8) ◽

pp. 4907-4913 ◽

Cited By ~ 21

Author(s):

Marieke G. G. Sturkenboom ◽

Leonie W. Mulder ◽

Arthur de Jager ◽

Richard van Altena ◽

Rob E. Aarnoutse ◽

...

Keyword(s):

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Mean Squared Error ◽

Geometric Mean ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Optimal Sampling ◽

Sampling Strategies ◽

Wide Range

ABSTRACTRifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0–24values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n= 1,000). The geometric mean AUC0–24value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with anr2value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC0–24in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

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