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Cilloniz, Catia; Torres, Antoni
doi: 10.1080/17425255.2023.2261376pmid: 37728376
Introduction Omadacycline is a new analog of the tetracycline class active against atypical bacteria, as well as against staphylococci, including methicillin-resistant strains, and Streptococcus pneumoniae. Areas covered This review has summarized the available clinical evidence on the use of oral omadacycline in the treatment of community-acquired pneumonia (CAP) and described the mechanism of action, pharmacokinetic/pharmacodynamic (PK/PD) parameters in healthy and special populations and the latest research on omadacycline. Expert opinion The available clinical evidence on oral omadacycline for the treatment of CAP shows that its properties provide reliable empirical coverage for pathogens such as Haemophilus influenzae, Moraxella catarrhalis, and species of Legionella, Chlamydia, and Mycoplasma. Omadacycline is also active against methicillin-resistant Staphylococcus aureus (MRSA); penicillin-resistant and multidrug-resistant Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae; and vancomycin-resistant Enterococcus spp. A dose of 450 mg orally once daily is recommended, followed by a maintenance dose of 300 mg orally once daily. Importantly, omadacycline does not require dose adjustment for patients based on BMI, age, gender, or renal or hepatic impairment.
Azuz, Samuel; Poulsen, Jakob Lykke; Vinter-Jensen, Lars; Olesen, Anne Estrup
doi: 10.1080/17425255.2023.2256216pmid: 37668362
Introduction Drug absorption is often altered and typically diminished in patients with short bowel syndrome (SBS). It is important to understand the patient’s gastrointestinal anatomy, the absorptive capacity of the remaining bowel, and the physicochemical and pharmacokinetic properties of the drug to optimize oral pharmacotherapy. Areas covered The primary focus was to provide an updated understanding of the absorption of various drugs in patients with short bowel syndrome. Forty-seven studies covering 13 different drug classes were included in the review and study details, patient characteristics, drug characteristics and pharmacokinetic findings were summarized for each drug class. Expert opinion Improving and simplifying drug treatment in patients with SBS have high priority, but the patients are multi diseased so knowledge regarding absorption of drugs as e.g. antithrombotic agents, immunosuppressants is urgently needed. Therefore, it is crucial to advance our understanding of the fundamental factors involved in drug absorption, spanning from drug design to pathophysiology. With the growing knowledge in drug design and gastrointestinal pathophysiology, we anticipate the development of computer models that can accurately predict optimal absorption in the future.
Chiew, Angela L.; Isbister, Geoffrey K.
doi: 10.1080/17425255.2023.2259787pmid: 37714812
Introduction Acetaminophen (paracetamol) is a commonly used analgesic and antipyretic agent, which is safe in therapeutic doses. Acetaminophen poisoning due to self-harm or repeated supratherapeutic ingestion is a common cause of acute liver injury. Acetylcysteine has been a mainstay of treatment for acetaminophen poisoning for decades and is efficacious if administered early. However, treatment failures occur if administered late, in ‘massive’ overdoses or in high-risk patients. Areas Covered This review provides an overview of the mechanisms of toxicity of acetaminophen poisoning (metabolic and oxidative phase) and how this relates to the assessment and treatment of the acetaminophen poisoned patient. The review focuses on how these advances offer further insight into the utility of novel biomarkers and the role of proposed adjunct treatments. Expert Opinion Advances in our understanding of acetaminophen toxicity have allowed the development of novel biomarkers and a better understanding of how adjunct treatments may prevent acetaminophen toxicity. Newly proposed adjunct treatments like fomepizole are being increasingly used without robust clinical trials. Novel biomarkers (not yet clinically available) may provide better assessment of these newly proposed adjunct treatments, particularly in clinical trials. These advances in our understanding of acetaminophen toxicity and liver injury hold promise for improved diagnosis and treatment.
Witkowska, Magdalena; Majchrzak, Agata; Robak, Paweł; Wolska-Washer, Anna; Robak, Tadeusz
doi: 10.1080/17425255.2023.2260305pmid: 37714711
Introduction Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors are a class of novel agents that are mainly used to treat B-cell malignancies. They function by inhibiting one or more enzymes which are part of the PI3K/AKT/mTOR pathway. Idelalisib is a first-in-class PI3Kδ inhibitor effective in patients with B-cell lymphoid malignancies. Areas covered This article reviews the chemical structure, mechanism of action, and metabolic and toxicological properties of PI3Kδ inhibitors and discusses their clinical applications in monotherapy and in combination with other agents for the treatment of chronic lymphocytic leukemia (CLL). A search was conducted of PubMed, Web of Science, and Google Scholar for articles in English. Results/Conclusion PI3Kδ inhibitors hold potential for the treatment of B-cell malignancies, including CLL. However, their use is also associated with severe toxicities, including pneumonia, cytopenias, hepatitis, and rash. Newer drugs are in development to reduce toxicity with novel schedules and/or combinations. Expert opinion The development of novel PI3Kδ inhibitors might help to reduce toxicity and improve efficacy in patients with CLL and other B-cell lymphoid malignancies.
Rybak, Leonard P.; Alberts, Ian; Patel, Shree; Al Aameri, Raheem F.H.; Ramkumar, Vickram
doi: 10.1080/17425255.2023.2260737pmid: 37728555
Introduction Cisplatin is a very effective chemotherapeutic agent against a variety of solid tumors. Unfortunately, cisplatin causes permanent sensorineural hearing loss in at least two-thirds of patients treated. There are no FDA approved drugs to prevent this serious side effect. Areas covered This paper reviews various natural products that ameliorate cisplatin ototoxicity. These compounds are strong antioxidants and anti-inflammatory agents. This review includes mostly preclinical studies but also discusses a few small clinical trials with natural products to minimize hearing loss from cisplatin chemotherapy in patients. The interactions of natural products with cisplatin in tumor-bearing animal models are highlighted. A number of natural products did not interfere with cisplatin anti-tumor efficacy and some agents actually potentiated cisplatin anti-tumor activity. Expert opinion There are a number of natural products or their derivatives that show excellent protection against cisplatin ototoxicity in preclinical studies. There is a need to insure uniform standards for purity of drugs derived from natural sources and to ensure adequate pharmacokinetics and safety of these products. Natural products that protect against cisplatin ototoxicity and augment cisplatin’s anti-tumor effects in multiple studies of tumor-bearing animals are most promising for advancement to clinical trials. The most promising natural products include honokiol, sulforaphane, and thymoquinone.
Cao, Bei; Huang, Lei; Liu, Ming; Lin, Hui; Ma, Tingting; Zhao, Yu; Geng, Yan; Yang, Yuanxun; Guo, Haifang; Li, Juan
doi: 10.1080/17425255.2023.2260738pmid: 37811634
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Background Limertinib is a novel mutant-selective and irreversible inhibitor of the epidermal growth factor receptor under development. A phase 1 open, two-period, single-sequence, self-controlled, two-part study was initiated to characterize the effects of a strong CYP3A4 inducer (rifampin) or inhibitor (itraconazole) on the pharmacokinetics of limertinib. Research design and methods Twenty-four healthy subjects in each part received a single dose of limertinib alone (160 mg, Part A; 80 mg, Part B) and with multiple doses of rifampin 600 mg once daily (Part A) or itraconazole 200 mg twice daily (Part B). Results Coadministration of rifampin decreased exposure (area under the plasma concentration-time curve from time 0 to infinity, AUC0-inf) of limertinib and its active metabolite CCB4580030 by 87.86% (geometric least-squares mean [GLSM] ratio, 12.14%; 90% confidence interval [CI], 9.89–14.92) and 66.82% (GLSM ratio, 33.18%; 90% CI, 27.72–39.72), respectively. Coadministration of itraconazole increased the AUC0-inf of limertinib by 289.8% (GLSM ratio, 389.8%; 90% CI, 334.07–454.82), but decreased that of CCB4580030 by 35.96% (GLSM ratio, 64.04%; 90% CI, 50.78–80.77). Conclusions Our study demonstrates that the concomitant use of limertinib with strong CYP3A inducers or inhibitors is not recommended. A single dose of limertinib, administered with or without rifampin or itraconazole, is generally safe and well tolerated in healthy Chinese subjects. Clinical trial registration www.clinicaltrials.gov identifier is NCT05631678.