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Australian Prescriber Feb 2016The pharmacokinetics of a drug may be altered in patients with renal impairment who require dialysis. Some drugs are contraindicated. The drug's clearance and... (Review)
Review
The pharmacokinetics of a drug may be altered in patients with renal impairment who require dialysis. Some drugs are contraindicated. The drug's clearance and therapeutic index determine if a dose adjustment is needed. A lower dose or less frequent dosing may be required. Consult a reference source or the patient's nephrologist before prescribing. Start at a low dose and increase gradually. If possible give once-daily drugs after dialysis.
PubMed: 27041803
DOI: 10.18773/austprescr.2016.008 -
Frontiers in Pharmacology 2022Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer... (Review)
Review
Despite the numerous scientific and technological advances made within the last decade the attrition rates for new drug discovery remain as high as 95% for anticancer drugs. Recent drug development has been in part guided by Lipinski's Rule of 5 (Ro5) even though many approved drugs do not comply to these rules. With Covid-19 vaccine development strategy dramatically accelerating drug development perhaps it is timely to question the generic drug development process itself to find a more efficient, cost effective, and successful approach. It is widely believed that drugs permeate cells via two methods: phospholipid bilayer diffusion and carrier mediated transporters. However, emerging evidence suggests that carrier mediated transport may be the primary mechanism of drug uptake and not diffusion as long believed. Computational biology increasingly assists drug design to achieve desirable absorption, distribution, metabolism, elimination and toxicity (ADMET) properties. Perfecting drug entry into target cells as a prerequisite to intracellular drug action is a logical and compelling route and is expected to reduce drug attrition rates, particularly gaining favour amongst chronic lifelong therapeutics. Novel drug development is rapidly expanding from the utilisation of beyond the rule of five (bRo5) to pulsatile drug delivery systems and fragment based drug design. Utilising transporters as drug targets and advocating bRo5 molecules may be the solution to increasing drug specificity, reducing dosage and toxicity and thus revolutionising drug development. This review explores the development of cell surface transporter exploitation in drug development and the relationship with improved therapeutic index.
PubMed: 35350751
DOI: 10.3389/fphar.2022.852938 -
Pharmaceuticals (Basel, Switzerland) Feb 2021Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors... (Review)
Review
Evolution of nanomedicine is the re-design of synthetic and biological carriers to implement novel theranostic platforms. In recent years, bacteriophage research favors this process, which has opened up new roads in drug and gene delivery studies. By displaying antibodies, peptides, or proteins on the surface of different bacteriophages through the phage display technique, it is now possible to unravel specific molecular determinants of both cancer cells and tumor-associated microenvironmental molecules. Downstream applications are manifold, with peptides being employed most of the times to functionalize drug carriers and improve their therapeutic index. Bacteriophages themselves were proven, in this scenario, to be good carriers for imaging molecules and therapeutics as well. Moreover, manipulation of their genetic material to stably vehiculate suicide genes within cancer cells substantially changed perspectives in gene therapy. In this review, we provide examples of how amenable phages can be used as anticancer agents, especially because their systemic administration is possible. We also provide some insights into how their immunogenic profile can be modulated and exploited in immuno-oncology for vaccine production.
PubMed: 33671476
DOI: 10.3390/ph14020161 -
Therapeutic Delivery Mar 2017Paul Ehrlich's 'magic bullet' concept has stimulated research for therapeutic agents with the capability to go straight to their intended targets. The 'magic bullet'... (Review)
Review
Paul Ehrlich's 'magic bullet' concept has stimulated research for therapeutic agents with the capability to go straight to their intended targets. The 'magic bullet' concept is still considered the ultimate approach to maximize the therapeutic effects of a given therapeutic agent without affecting nontargeted tissues. But so far, there has never been a therapeutic agent or a delivery system that goes straight to the target in the body, and no approach has provided anything better than just a few percents of the total administered dose reaching the intended target sites. But engineering principles can transform systematically circulating vectors that so far were based primarily on physical characteristics and biochemical principles alone, as smart therapeutic agents with the required propulsion-navigation-homing capabilities to enable them to go straight to their intended targets.
Topics: Drug Delivery Systems; Humans; Neoplasms
PubMed: 28361606
DOI: 10.4155/tde-2016-0088 -
International Journal of Surgery... May 2022Pancreaticoduodenectomy (PD) is a challenging procedure with peri-operative complications. Robotic surgery offers improved dexterity, visibility, and accessibility.... (Review)
Review
BACKGROUND
Pancreaticoduodenectomy (PD) is a challenging procedure with peri-operative complications. Robotic surgery offers improved dexterity, visibility, and accessibility. Recently, many centres have reported improved clinical outcomes for robotic PD. We reviewed the safety and efficacy of robotic PD in comparison to open PD using 'Therapeutic Index' (TI).
METHODS
A systematic review of the literature was conducted in various databases. Articles published between January 2010 and March 2021 reporting totally-robotic and open PD were included, according to the PRISMA and AMSTAR-2 guidelines. The Cochrane tool was used for risk of bias assessment. We compared 30-day mortality rates (MR), lymphadenectomy rates (LR), R0 resection rates (RRR) and therapeutic index (TI). STATA 16.1 was used for statistical analysis.
RESULTS
The four studies that met inclusion criteria included 5090 PDs, out of which 617 were totally-robotic (RPD) and 4473 were open (OPD). Variance ratio tests demonstrated a)Higher TI for RPD versus OPD (1807.42 vs 1723.37, p = 0.86), b)Significantly smaller MR (2.50 vs 19.00, p = 0.0004), c)Significantly lower RRR (130.50 vs 939.25, p = 0.00) and d)No significant difference in LR between RPD and OPD (35.63 vs 38.25, p = 0.81). Meta-regression analysis showed a significantly higher TI coefficient of RPD than OPD (0.66 vs -0.40, p = 0.08, α = 0.1).
CONCLUSION
Our study suggests that robotic PD is safe and not inferior to open PD and our analysis RPD demonstrated a higher therapeutic index than OPD. Randomised controlled trials are required to establish the efficacy of robotic PD. Also, standardisation of reporting mortality, survival and oncological outcomes is needed for the effective calculation of TI.
Topics: Humans; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Postoperative Complications; Retrospective Studies; Robotic Surgical Procedures; Therapeutic Index
PubMed: 35487420
DOI: 10.1016/j.ijsu.2022.106633 -
Postgraduate Medical Journal Feb 2005Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine... (Review)
Review
Artemisinins were discovered to be highly effective antimalarial drugs shortly after the isolation of the parent artemisinin in 1971 in China. These compounds combine potent, rapid antimalarial activity with a wide therapeutic index and an absence of clinically important resistance. Artemisinin containing regimens meet the urgent need to find effective treatments for multidrug resistant malaria and have recently been advocated for widespread deployment. Comparative trials of artesunate and quinine for severe malaria are in progress to see if the persistently high mortality of this condition can be reduced.
Topics: Antimalarials; Artemisinins; Humans; Malaria
PubMed: 15701735
DOI: 10.1136/pgmj.2004.028399 -
Clinical Neuropharmacology 2016Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs):... (Review)
Review
OBJECTIVES
Our study aimed to determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate.
METHODS
We performed a literature search using PubMed and EMBASE to collect published safety, efficacy, and therapeutic monitoring data for 5 AEDs and extracted all relevant information into a drug- and study-specific drug database. For each AED, we summarized (1) type, severity, and incidence of toxicity-related adverse events and toxicity-associated range of drug doses or concentrations; (2) effective versus toxic concentration and dose (therapeutic range); and (3) therapeutic drug monitoring practices. We defined therapeutic index as the ratio of the minimum toxic concentration to the minimum effective concentration.
RESULTS
We reviewed a total of 810 full-text articles and extracted data from 163. The literature suggests that the therapeutic index of phenytoin is 2. The therapeutic indices of phenobarbital and valproate exceed 2. There were insufficient data to precisely quantify the therapeutic indices of carbamazepine and lamotrigine.
CONCLUSIONS
For some drugs, this approach offers a low-cost method of therapeutic index estimation. Our results can serve as preliminary data for future trials and as guidance for US Food and Drug Administration decision making regarding narrow therapeutic index classification.
Topics: Anticonvulsants; Databases, Bibliographic; Drug Monitoring; Epilepsy; Humans; Treatment Outcome
PubMed: 27428884
DOI: 10.1097/WNF.0000000000000172 -
P & T : a Peer-reviewed Journal For... Aug 2009Warfarin, an anticoagulant, is used to prevent and treat thromboembolic disease. One of the drawbacks of this agent, also known as Coumadin (Bristol-Myers Squibb), is...
Warfarin, an anticoagulant, is used to prevent and treat thromboembolic disease. One of the drawbacks of this agent, also known as Coumadin (Bristol-Myers Squibb), is that it is difficult to administer at the correct dose as a result of its narrow therapeutic index, its tendency to cause bleeding, and the individual variability in patient response. Achieving safe and effective doses of warfarin therapy is both an urgent and important concern for many clinicians.Recent research has focused on single-nucleotide polymorphisms (SNPs) of genes that encode two proteins: the cytochrome P450 2C9 enzyme and VKORC1 (vitamin K epoxide reductase complex). Studies suggest that CYP 2C9 influences warfarin metabolism, whereas VKORC1 plays a role in the pharmacodynamic response in expression of the enzymatic target of warfarin. Patients who carry CYP 2C9*2 and CYP 2C9*3 alleles tend to require lower warfarin maintenance doses because of their slowed metabolism compared with patients who carry the "wild-type" allele. Patients who carry the VKORC1 A haplotype tend to require lower wafarin maintenance doses as a result of a decreased expression of messenger RNA (mRNA), which produces the proteins necessary for the formation of VKORC1.
PubMed: 20140106
DOI: No ID Found -
MAbs 2022Antibody-drug conjugates (ADCs) are increasingly powerful medicines for targeted cancer therapy. Inspired by the trend to further improve their therapeutic index by...
Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering.
Antibody-drug conjugates (ADCs) are increasingly powerful medicines for targeted cancer therapy. Inspired by the trend to further improve their therapeutic index by generation of homogenous ADCs, we report here how the clinical-stage GlycoConnect™ technology uses the globally conserved -glycosylation site to generate stable and site-specific ADCs based on enzymatic remodeling and metal-free click chemistry. We demonstrate how an engineered endoglycosidase and a native glycosyl transferase enable highly efficient, one-pot glycan remodeling, incorporating a novel sugar substrate 6-azidoGalNAc. Metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants. The therapeutic potential of GlycoConnect™, in combination with HydraSpace™ polar spacer technology, was compared to that of Kadcyla® (ado-trastuzumab emtansine), showing significantly improved efficacy and tolerability.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents; Immunoconjugates; Polysaccharides; Therapeutic Index
PubMed: 35634725
DOI: 10.1080/19420862.2022.2078466 -
Small (Weinheim An Der Bergstrasse,... May 2015Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity... (Review)
Review
Aptamers are composed of short RNA or single-stranded DNA sequences that, when folded into their unique 3D conformation, can bind to their targets with high specificity and affinity. Although functionally similar to protein antibodies, oligonucleotide aptamers offer several advantages over protein antibodies in biomedical and clinical applications. Through the enhanced permeability and retention effect, nanomedicines can improve the therapeutic index of a treatment and reduce side effects by enhancing accumulation at the disease site. However, this targets tumors passively and, thus, may not be ideal for targeted therapy. To construct ligand-directed "active targeting" nanobased delivery systems, aptamer-equipped nanomedicines have been tested for in vitro diagnosis, in vivo imaging, targeted cancer therapy, theranostic approaches, sub-cellular molecule detection, food safety, and environmental monitoring. This review focuses on the development of aptamer-conjugated nanomedicines and their application for in vivo imaging, targeted therapy, and theranostics.
Topics: Aptamers, Nucleotide; Drug Delivery Systems; Humans; Nanomedicine; Theranostic Nanomedicine
PubMed: 25677591
DOI: 10.1002/smll.201403073