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The American Journal of Managed Care Sep 2011Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be... (Review)
Review
Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.
Topics: Analgesics, Opioid; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Managed Care Programs; Pharmacogenetics
PubMed: 21999760
DOI: No ID Found -
Chemical & Pharmaceutical Bulletin 2019A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular... (Review)
Review
A major limitation of traditional chemotherapy for cancer is dose-limiting toxicity, caused by the exposure of non-tumor cells to cytotoxic agents. Use of molecular targeted drugs, such as specific kinase inhibitors and monoclonal antibodies, is a possible solution to overcome this limitation and has achieved clinical success so far. Use of an antibody-drug conjugate (ADC) is a rational strategy for improving efficacy and reducing systemic adverse events. ADCs use antibodies selectively to deliver a potent cytotoxic agent to tumor cells, thus drastically improving the therapeutic index of chemotherapeutic agents. Lessons learned from clinical failure of early ADCs during the 1980s to 90s have recently led to improvements in ADC technology, and resulted in the approval of four novel ADCs. Nonetheless, further advances in ADC technology are still required to streamline their clinical efficacy and reduce toxicity. [fam-] Trastuzumab deruxtecan (DS-8201a) is a next-generation ADC that satisfies these requirements based on currently available evidence. DS-8201a has several innovative features; a highly potent novel payload with a high drug-to-antibody ratio, good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo; the released cytotoxic payload could exert a bystander effect. With respect to its preclinical profiles, DS-8201a could provide a valuable therapy with a great potential against HER2-expressing cancers in clinical settings. In a phase I trial, DS-8201a showed acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Camptothecin; Cell Line, Tumor; Drug Development; Genes, erbB-2; Humans; Immunoconjugates; Molecular Targeted Therapy; Neoplasms; Topoisomerase I Inhibitors; Trastuzumab
PubMed: 30827997
DOI: 10.1248/cpb.c18-00744 -
British Journal of Clinical Pharmacology Sep 2015Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies.... (Review)
Review
Glucocorticosteroids are a group of structurally related molecules that includes natural hormones and synthetic drugs with a wide range of anti-inflammatory potencies. For synthetic corticosteroid analogues it is commonly assumed that the therapeutic index cannot be improved by increasing their glucocorticoid receptor binding affinity. The validity of this assumption, particularly for inhaled corticosteroids, has not been fully explored. Inhaled corticosteroids exert their anti-inflammatory activity locally in the airways, and hence this can be dissociated from their potential to cause systemic adverse effects. The molecular structural features that increase glucocorticoid receptor binding affinity and selectivity drive topical anti-inflammatory activity. However, in addition, these structural modifications also result in physicochemical and pharmacokinetic changes that can enhance targeting to the airways and reduce systemic exposure. As a consequence, potency and therapeutic index can be correlated. However, this consideration is not reflected in asthma treatment guidelines that classify inhaled corticosteroid formulations as low-, mid- and high dose, and imbed a simple dose equivalence approach where potency is not considered to affect the therapeutic index. This article describes the relationship between potency and therapeutic index, and concludes that higher potency can potentially improve the therapeutic index. Therefore, both efficacy and safety should be considered when classifying inhaled corticosteroid regimens in terms of dose equivalence. The historical approach to dose equivalence in asthma treatment guidelines is not appropriate for the wider range of molecules, potencies and device/formulations now available. A more robust method is needed that incorporates pharmacological principles.
Topics: Administration, Inhalation; Anti-Inflammatory Agents; Glucocorticoids; Humans; Molecular Structure; Protein Binding; Receptors, Glucocorticoid; Therapeutic Equivalency
PubMed: 25808113
DOI: 10.1111/bcp.12637 -
The Western Journal of Emergency... Jan 2015Historically, most patients who required parenteral anticoagulation received heparin, whereas those patients requiring oral anticoagulation received warfarin. Due to the... (Review)
Review
Historically, most patients who required parenteral anticoagulation received heparin, whereas those patients requiring oral anticoagulation received warfarin. Due to the narrow therapeutic index and need for frequent laboratory monitoring associated with warfarin, there has been a desire to develop newer, more effective anticoagulants. Consequently, in recent years many novel anticoagulants have been developed. The emergency physician may institute anticoagulation therapy in the short term (e.g. heparin) for a patient being admitted, or may start a novel anticoagulation for a patient being discharged. Similarly, a patient on a novel anticoagulant may present to the emergency department due to a hemorrhagic complication. Consequently, the emergency physician should be familiar with the newer and older anticoagulants. This review emphasizes the indication, mechanism of action, adverse effects, and potential reversal strategies for various anticoagulants that the emergency physician will likely encounter.
Topics: Anticoagulants; Antithrombins; Embolism; Emergency Service, Hospital; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Thrombosis; Warfarin
PubMed: 25671002
DOI: 10.5811/westjem.2014.12.22933 -
CA: a Cancer Journal For Clinicians Sep 2019Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is... (Review)
Review
Brachytherapy is a specific form of radiotherapy consisting of the precise placement of radioactive sources directly into or next to the tumor. This technique is indicated for patients affected by various types of cancers. It is an optimal tool for delivering very high doses to the tumor focally while minimizing the probability of normal tissue complications. Physicians from a wide range of specialties may be involved in either the referral to or the placement of brachytherapy. Many patients require brachytherapy as either primary treatment or as part of their oncologic care. On the basis of high-level evidence from randomized controlled trials, brachytherapy is mainly indicated: 1) as standard in combination with chemoradiation in patients with locally advanced cervical cancer; 2) in surgically treated patients with uterine endometrial cancer for decreasing the risk of vaginal vault recurrence; 3) in patients with high-risk prostate cancer to perform dose escalation and improve progression-free survival; and 4) in patients with breast cancer as adjuvant, accelerated partial breast irradiation or to boost the tumor bed. In this review, the authors discuss the clinical relevance of brachytherapy with a focus on indications, levels of evidence, and results in the overall context of radiation use for patients with cancer.
Topics: Antineoplastic Agents; Brachytherapy; Chemoradiotherapy; Disease Progression; Dose Fractionation, Radiation; Education, Medical, Continuing; Evidence-Based Medicine; Humans; Neoadjuvant Therapy; Neoplasms; Patient Selection; Physicians; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 31361333
DOI: 10.3322/caac.21578 -
Pharmaceutics Mar 2017Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid... (Review)
Review
Liposomes are the first nano drug delivery systems that have been successfully translated into real-time clinical applications. These closed bilayer phospholipid vesicles have witnessed many technical advances in recent years since their first development in 1965. Delivery of therapeutics by liposomes alters their biodistribution profile, which further enhances the therapeutic index of various drugs. Extensive research is being carried out using these nano drug delivery systems in diverse areas including the delivery of anti-cancer, anti-fungal, anti-inflammatory drugs and therapeutic genes. The significant contribution of liposomes as drug delivery systems in the healthcare sector is known by many clinical products, e.g., Doxil, Ambisome, DepoDur™, etc. This review provides a detailed update on liposomal technologies e.g., DepoFoam™ Technology, Stealth technology, etc., the formulation aspects of clinically used products and ongoing clinical trials on liposomes.
PubMed: 28346375
DOI: 10.3390/pharmaceutics9020012 -
British Journal of Clinical Pharmacology Feb 2021To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity,... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity, physicochemical and pharmacokinetic properties.
METHODS
This escalating-dose, placebo-controlled, cross-over study randomised adults with asthma to 1 or 2 treatment periods with ≥25 days washout in-between. Each treatment period comprised five 7-day dose escalations (μg/d): fluticasone furoate (FF; 25 → 100 → 200 → 400 → 800), fluticasone propionate (FP; 50 → 200 → 500 → 1000 → 2000), budesonide (BUD; 100 → 400 → 800 → 1600 → 3200) or placebo. Airway hyperresponsiveness to adenosine-5'-monophosphate (AMP PC ) was assessed on day 8. Plasma cortisol was assessed on day 1 (predose baseline) and from pre-PM dose on day 6 to pre-PM dose day 7 (24-h weighted mean).
RESULTS
Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC dose at which 50% of the maximum effect is achieved [ED ] values: 48.52, 1081.27 and 1467.36 μg/d, respectively). Systemic activity (cortisol suppression) ED values were 899.99, 1986.05 and 1927.42 μg/d, respectively. The therapeutic index (ED cortisol suppression/ED AMP PC ) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 μg/d and 200 μg/d were both comparable in terms of airway potency with high doses of FP (≥1000 μg twice daily [BID]) and BUD (≥1500 μg/BID). The systemic activity of FF 100 μg/d and 200 μg/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 μg/BID and 250 μg/BID) and BUD (100 μg/BID and 200 μg/BID).
CONCLUSION
This study provides evidence that FF can provide more protection against airway hyperresponsiveness, with less systemic activity, than FP or BUD. This suggests that all inhaled corticosteroids are not therapeutically similar and may differ in their therapeutic index. (203162; NCT02991859).
Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Cross-Over Studies; Double-Blind Method; Fluticasone; Humans; Hydrocortisone; Therapeutic Index
PubMed: 32484940
DOI: 10.1111/bcp.14406 -
MAbs 2016Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics. Their design involves a tumor-specific antibody, a linker and a cytotoxic payload. They... (Review)
Review
Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics. Their design involves a tumor-specific antibody, a linker and a cytotoxic payload. They were designed to allow specific targeting of highly potent cytotoxic agents to tumor cells whilst sparing normal cells. Frequent toxicities that may be driven by any of the components of an ADC have been reported. There are currently more than 50 ADCs in active clinical development, and a further ∼20 that have been discontinued. For this review, the reported toxicities of ADCs were analysed, and the mechanisms for their effects are explored in detail. Methods to reduce toxicities, including dosing strategies and drug design, are discussed. The toxicities reported for active and discontinued drugs are important to drive the rational design and improve the therapeutic index of ADCs of the future.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Humans; Immunoconjugates; Neoplasms
PubMed: 27045800
DOI: 10.1080/19420862.2016.1156829 -
Ochsner Journal 2013Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions....
BACKGROUND
Owing to the low therapeutic index of barbiturates, benzodiazepines (BZDs) became popular in this country and worldwide many decades ago for a wide range of conditions. Because of an increased understanding of pharmacology and physiology, the mechanisms of action of many BZDs are now largely understood, and BZDs of varying potency and duration of action have been developed and marketed. Although BZDs have many therapeutic roles and BZD-mediated effects are typically well tolerated in the general population, side effects and toxicity can result in morbidity and mortality for some patients. The elderly; certain subpopulations of patients with lung, liver, or kidney dysfunction; and patients on other classes of medication are especially prone to toxicity.
METHODS
This review details the present knowledge about BZD mechanisms of action, drug profiles, clinical actions, and potential side effects. In addition, this review describes numerous types of BZD-mediated central nervous system effects.
CONCLUSION
For any patient taking a BZD, the prescribing physician must carefully evaluate the risks and benefits, and higher-risk patients require careful considerations. Clinically appropriate use of BZDs requires prudence and the understanding of pharmacology.
PubMed: 23789008
DOI: No ID Found