-
Expert Review of Clinical Pharmacology 2023Pediatric attention-deficit disorder (ADHD) impacts a significant percentage of the population world-wide. Pharmacologic treatments have been shown to be safe and... (Review)
Review
INTRODUCTION
Pediatric attention-deficit disorder (ADHD) impacts a significant percentage of the population world-wide. Pharmacologic treatments have been shown to be safe and effective for managing symptoms. Various medication formulations exist, and new medication agents are continually approved each year.
AREAS COVERED
This article offers an overview of ADHD, an overview of both stimulant and non-stimulant medication options as well as an overview of stimulant misuse. It explores the medication mechanisms of action and side effect profiles, as well as offering an in-depth summary of the novel agents recently approved and soon-to-be approved for use in youth. PubMed and Medline were utilized. Search terms included children, adolescents, ADHD, and medication. FDA package inserts were reviewed for all medications.
EXPERT OPINION
New formulations of medications include an evening administered, extended, and delayed-release form of methylphenidate (DR/ER MPH), a methylphenidate pro-drug (serdexmethylphenidate) and an amphetamine patch. The availability of a new SNRI (selective norepinephrine reuptake inhibitor), viloxazine extended-release (VER), and the pending approval of a triple reuptake inhibitor (centanafadine) provides welcome additions to the prescriber's toolbox.
Topics: Adolescent; Humans; Child; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Methylphenidate; Amphetamine; Prodrugs
PubMed: 37587841
DOI: 10.1080/17512433.2023.2249414 -
Nature Communications Jul 2023The often immune-suppressive tumor microenvironment (TME) may hinder immune evasion and response to checkpoint blockade therapies. Pharmacological activation of the...
The often immune-suppressive tumor microenvironment (TME) may hinder immune evasion and response to checkpoint blockade therapies. Pharmacological activation of the STING pathway does create an immunologically hot TME, however, systemic delivery might lead to undesired off-target inflammatory responses. Here, we generate a small panel of esterase-activatable pro-drugs based on the structure of the non-nucleotide STING agonist MSA-2 that are subsequently stably incorporated into a liposomal vesicle for intravenous administration. The pharmacokinetic properties and immune stimulatory capacity of pro-drugs delivered via liposomes (SAProsomes) are enhanced compared to the free drug form. By performing efficacy screening among the SAProsomes incorporating different pro-drugs in syngeneic mouse tumor models, we find that superior therapeutic performance relies on improved delivery to the desired tumor and lymphoid compartments. The best candidate, SAProsome-3, highly stimulates secretion of inflammatory cytokines and creates a tumoricidal immune landscape. Notably, upon application to breast cancer or melanoma mouse models, SAProsome-3 elicits durable remission of established tumors and postsurgical tumor-free survival while decreasing metastatic burden without significant systemic toxicity. In summary, our work establishes the proof of principle for a better targeted and more efficient and safe STING agonist therapy.
Topics: Animals; Mice; Liposomes; Prodrugs; Melanoma; Cell Line, Tumor; Tumor Microenvironment; Immunotherapy
PubMed: 37524727
DOI: 10.1038/s41467-023-40312-y -
Nature Reviews. Drug Discovery May 2024Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration... (Review)
Review
Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs encompass a wide range of different chemical structures, therapeutic indications and properties. Here we provide the first holistic analysis of the current landscape of approved prodrugs using cheminformatics and data science approaches to reveal trends in prodrug development. We highlight rationales that underlie prodrug design, their indications, mechanisms of API release, the chemistry of promoieties added to APIs to form prodrugs and the market impact of prodrugs. On the basis of this analysis, we discuss strengths and limitations of current prodrug approaches and suggest areas for future development.
Topics: Prodrugs; Humans; Animals; Drug Design; Drug Development
PubMed: 38565913
DOI: 10.1038/s41573-024-00914-7 -
Advanced Materials (Deerfield Beach,... May 2024Neuroinflammation has emerged as a major concern in ischemic stroke therapy because it exacebates neurological dysfunction and suppresses neurological recovery after...
Neuroinflammation has emerged as a major concern in ischemic stroke therapy because it exacebates neurological dysfunction and suppresses neurological recovery after ischemia/reperfusion. Fingolimod hydrochloride (FTY720) is an FDA-approved anti-inflammatory drug which exhibits potential neuroprotective effects in ischemic brain parenchyma. However, delivering a sufficient amount of FTY720 through the blood-brain barrier into brain lesions without inducing severe cardiovascular side effects remains challenging. Here, a neutrophil membrane-camouflaged polyprodrug nanomedicine that can migrate into ischemic brain tissues and in situ release FTY720 in response to elevated levels of reactive oxygen species. This nanomedicine delivers 15.2-fold more FTY720 into the ischemic brain and significantly reduces the risk of cardiotoxicity and infection compared with intravenously administered free drug. In addition, single-cell RNA-sequencing analysis identifies that the nanomedicine attenuates poststroke inflammation by reprogramming microglia toward anti-inflammatory phenotypes, which is realized via modulating Cebpb-regulated activation of NLRP3 inflammasomes and secretion of CXCL2 chemokine. This study offers new insights into the design and fabrication of polyprodrug nanomedicines for effective suppression of inflammation in ischemic stroke therapy.
Topics: Animals; Ischemic Stroke; Nanomedicine; Mice; Neutrophils; Fingolimod Hydrochloride; Inflammation; Prodrugs; NLR Family, Pyrin Domain-Containing 3 Protein; Cell Membrane; Anti-Inflammatory Agents; Reactive Oxygen Species; Microglia; Humans; Neuroprotective Agents
PubMed: 38519052
DOI: 10.1002/adma.202311803 -
Advanced Materials (Deerfield Beach,... Jan 2024Both cisplatin-based chemotherapy and immune checkpoint blockers (ICBs)-based immunotherapy are the first-line treatments for patients with advanced bladder cancer....
Targeting DNA Damage and Repair Machinery via Delivering WEE1 Inhibitor and Platinum (IV) Prodrugs to Stimulate STING Pathway for Maximizing Chemo-Immunotherapy in Bladder Cancer.
Both cisplatin-based chemotherapy and immune checkpoint blockers (ICBs)-based immunotherapy are the first-line treatments for patients with advanced bladder cancer. Cancer cells can develop resistance to cisplatin through extensive DNA repair, while a low response rate to ICBs is mostly due to the presence of an immunosuppressive microenvironment and low PD-L1 expression. Herein, a glutathione (GSH)-responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) is designed. NP2 can be triggered by GSH in cancer cells, and the released MK1775 can inhibit the activity of WEE1 protein, which ultimately increases DNA damage by cisplatin. Genome-wide RNA sequencing first reveals that NP2 can inhibit DNA repair machinery by interfering with the cell cycle and significantly activate the stimulator of interferon genes pathway. Tumor growth is significantly inhibited by NP2 in vivo. As innate and adaptive immune responses are stimulated, the immunosuppressive microenvironment is modified, and the "immune cold tumor" is transformed into an "immune hot tumor". In addition, NP2 can upregulate PD-L1 expression in tumor cells, thereby increasing the response rate of PD-L1 monoclonal antibody (αPD-L1) and eliciting long-term immune responses in both primary and metastatic tumors.
Topics: Humans; Cisplatin; Platinum; B7-H1 Antigen; Prodrugs; Urinary Bladder Neoplasms; DNA Damage; Immunotherapy; Tumor Microenvironment; Cell Line, Tumor; Protein-Tyrosine Kinases; Cell Cycle Proteins
PubMed: 37849029
DOI: 10.1002/adma.202308762 -
Nanoscale Nov 2023Camptothecin (CPT) is a cytotoxic alkaloid that attenuates the replication of cancer cells blocking DNA topoisomerase 1. Despite its encouraging and wide-spectrum... (Review)
Review
Camptothecin (CPT) is a cytotoxic alkaloid that attenuates the replication of cancer cells blocking DNA topoisomerase 1. Despite its encouraging and wide-spectrum antitumour activity, its application is significantly restricted owing to its instability, low solubility, significant toxicity, and acquired tumour cell resistance. This has resulted in the development of many CPT-based therapeutic agents, especially CPT-based nanomedicines, with improved pharmacokinetic and pharmacodynamic profiles. Specifically, smart CPT-based prodrug nanomedicines with stimuli-responsive release capacity have been extensively explored owing to the advantages such as high drug loading, improved stability, and decreased potential toxicity caused by the carrier materials in comparison with normal nanodrugs and traditional delivery systems. In this review, the potential strategies and applications of CPT-based nanoprodrugs for enhanced CPT delivery toward cancer cells are summarized. We appraise in detail the chemical structures and release mechanisms of these nanoprodrugs and guide materials chemists to develop more powerful nanomedicines that have real clinical therapeutic capacities.
Topics: Prodrugs; Drug Delivery Systems; Camptothecin; Nanomedicine; Antineoplastic Agents; Cell Line, Tumor; Nanoparticles; Neoplasms
PubMed: 37909755
DOI: 10.1039/d3nr04147f -
Chembiochem : a European Journal of... Sep 2023Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs... (Review)
Review
Prodrugs are pharmacologically inactive, chemically modified derivatives of active drugs, which, following in vivo administration, are converted to the parent drugs through chemical or enzymatic cleavage. The prodrug approach holds tremendous potential to create the enhanced version of an existing pharmacological agent and leverage those improvements to augment the drug molecules' bioavailability, targeting ability, therapeutic efficacy, safety, and marketability. Especially in cancer therapy, prodrug application has received substantial attention. A prodrug can effectively broaden the therapeutic window of its parent drug by enhancing its release at targeted tumor sites while reducing its access to healthy cells. The spatiotemporally controlled release can be achieved by manipulating the chemical, physical, or biological stimuli present at the targeted tumor site. The critical strategy comprises drug-carrier linkages that respond to physiological or biochemical stimuli in the tumor milieu to yield the active drug form. This review will focus on the recent advancements in the development of various fluorophore-drug conjugates that are widely used for real-time monitoring of drug delivery. The use of different stimuli-cleavable linkers and the mechanisms of linker cleavage will be discussed. Finally, the review will conclude with a critical discussion of the prospects and challenges that might impede the future development of such prodrugs.
Topics: Humans; Prodrugs; Drug Delivery Systems; Drug Carriers; Neoplasms
PubMed: 37341379
DOI: 10.1002/cbic.202300155 -
Chemical Society Reviews Nov 2023Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The... (Review)
Review
Prodrugs have emerged as a major strategy for addressing clinical challenges by improving drug pharmacokinetics, reducing toxicity, and enhancing treatment efficacy. The emergence of new bioorthogonal chemistry has greatly facilitated the development of prodrug strategies, enabling their activation through chemical and physical stimuli. This "on-demand" activation using bioorthogonal chemistry has revolutionized the research and development of prodrugs. Consequently, prodrug activation has garnered significant attention and emerged as an exciting field of translational research. This review summarizes the latest advancements in prodrug activation by utilizing bioorthogonal chemistry and mainly focuses on the activation of small-molecule prodrugs and antibody-drug conjugates. In addition, this review also discusses the opportunities and challenges of translating these advancements into clinical practice.
Topics: Prodrugs
PubMed: 37905601
DOI: 10.1039/d2cs00889k -
Journal of Inorganic Biochemistry May 2024Platinum-based anticancer drugs, while potent, are associated with numerous and severe side effects. Hyperthermia therapy is an effective adjuvant in anticancer...
Platinum-based anticancer drugs, while potent, are associated with numerous and severe side effects. Hyperthermia therapy is an effective adjuvant in anticancer treatment, however, clinically used platinum drugs have not been optimised for combination with hyperthermia. The derivatisation of existing anticancer drugs with appropriately chosen thermoresponsive moieties results in drugs being activated only at the heated site. Perfluorinated chains of varying lengths were installed on carboplatin, a clinically approved drug, leading to the successful synthesis of a series of mono- and di- substituted platinum(IV) carboplatin prodrugs. Some of these complexes display relevant thermosensitivity on ovarian cancer cell lines, i.e., being inactive at 37 °C while having comparable activity to carboplatin under mild hyperthermia (42 °C). Nuclear magnetic resonance spectroscopy and mass spectrometry indicated that carboplatin is likely the active platinum(II) anticancer agent upon reduction and cyclic voltammetry revealed that the length of the fluorinated alkyl chain has a strong influence on the rate of carboplatin formation, regulating the subsequent cytotoxicity.
Topics: Female; Humans; Carboplatin; Prodrugs; Antineoplastic Agents; Ovarian Neoplasms; Platinum; Cisplatin
PubMed: 38377623
DOI: 10.1016/j.jinorgbio.2024.112505 -
Advanced Drug Delivery Reviews Jul 2023Long-acting formulations are designed to reduce dosing frequency and simplify dosing schedules by providing an extended duration of action. One approach to obtain... (Review)
Review
Long-acting formulations are designed to reduce dosing frequency and simplify dosing schedules by providing an extended duration of action. One approach to obtain long-acting formulations is to combine long-acting prodrugs (LA-prodrug) with existing or emerging drug delivery technologies (DDS). The design criteria for long-acting prodrugs are distinct from conventional prodrug strategies that alter absorption, distribution, metabolism, and excretion (ADME) parameters. Our review focuses on long-acting prodrug delivery systems (LA-prodrug DDS), which is a subcategory of long-acting formulations where prodrug design enables DDS formulation to achieve an extended duration of action that is greater than the parent drug. Here, we define LA-prodrugs as the conjugation of an active pharmaceutical ingredient (API) to a promoiety group via a cleavable covalent linker, where both the promoiety and linker are selected to enable formulation and administration from a drug delivery system (DDS) to achieve an extended duration of action. These LA-prodrug DDS results in an extended interval where the API is within a therapeutic range without necessarily altering ADME as is typical of conventional prodrugs. The conversion of the LA-prodrug to the API is dependent on linker cleavage, which can occur before or after release from the DDS. The requirement for linker cleavage provides an additional tool to prolong release from these LA-prodrug DDS. In addition, the physicochemical properties of drugs can be tuned by promoiety selection for a particular DDS. Conjugation with promoieties that are carriers or amenable to assembly into carriers can also provide access to formulations designed for extending duration of action. LA-prodrugs have been applied to a wide variety of drug delivery strategies and are categorized in this review by promoiety size and complexity. Small molecule promoieties (typically MW < 1000 Da) have been used to improve encapsulation or partitioning as well as broaden APIs for use with traditional long-acting formulations such as solid drug dispersions. Macromolecular promoieties (typically MW > 1000 Da) have been applied to hydrogels, nanoparticles, micelles, dendrimers, and polymerized prodrug monomers. The resulting LA-prodrug DDS enable extended duration of action for active pharmaceuticals across a wide range of applications, with target release timescales spanning days to years.
Topics: Humans; Prodrugs; Drug Delivery Systems
PubMed: 37160248
DOI: 10.1016/j.addr.2023.114860