Can we Predict Drug Excretion into Saliva? A Systematic Review and Analysis of Physicochemical Properties.

BACKGROUND AND OBJECTIVES: Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM. METHODS: Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool. RESULTS: Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = - 0.76, p = 0.01) and polar surface area (R = - 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = - 0.65, p = 0.04) and hydrogen bond donor count (R = - 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias. CONCLUSIONS: Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach to improve patient outcomes.

New Oxazolidinones for Tuberculosis: Are Novel Treatments on the Horizon?

Multidrug-resistant tuberculosis (MDR-TB) is a global health concern. Standard treatment involves the use of linezolid, a repurposed oxazolidinone. It is associated with severe adverse effects, including myelosuppression and mitochondrial toxicity. As such, it is imperative to identify novel alternatives that are better tolerated but equally or more effective. Therefore, this review aims to identify and explore the novel alternative oxazolidinones to potentially replace linezolid in the management of TB. The keywords tuberculosis and oxazolidinones were searched in PubMed to identify eligible compounds. The individual drug compounds were then searched with the term tuberculosis to identify the relevant in vitro, in vivo and clinical studies. The search identified sutezolid, tedizolid, delpazolid, eperezolid, radezolid, contezolid, posizolid and TBI-223, in addition to linezolid. An additional search resulted in 32 preclinical and 21 clinical studies. All novel oxazolidinones except posizolid and eperezolid resulted in positive preclinical outcomes. Sutezolid and delpazolid completed early phase 2 clinical studies with better safety and equal or superior efficacy. Linezolid is expected to continue as the mainstay therapy, with renewed interest in drug monitoring. Sutezolid, tedizolid, delpazolid and TBI-223 displayed promising preliminary results. Further clinical studies would be required to assess the safety profiles and optimize the dosing regimens.

Reducing hand radiation during renal access for percutaneous nephrolithotomy: a comparison of radiation reduction techniques.

Percutaneous nephrolithotomy confers the highest radiation to the urologist's hands compared to other urologic procedures. This study compares radiation exposure to the surgeon's hand and patient's body when utilizing three different techniques for needle insertion during renal access. Simulated percutaneous renal access was performed using a cadaveric patient and separate cadaveric forearm representing the surgeon's hand. Three different needle-holding techniques were compared: conventional glove (control), a radiation-attenuating glove, and a novel needle holder. Five 300-s fluoroscopy trials were performed per treatment arm. The primary outcome was radiation dose (mSv) to the surgeon's hand. The secondary outcome was radiation dose to the patient. One-way ANOVA and Tukey's B post-hoc tests were performed with p < 0.05 considered significant. Compared to the control (3.92 mSv), both the radiation-attenuating glove (2.48 mSv) and the needle holder (1.37 mSv) reduced hand radiation exposure (p < 0.001). The needle holder reduced hand radiation compared to the radiation-attenuating glove (p < 0.001). The radiation-attenuating glove resulted in greater radiation produced by the C-arm compared to the needle holder (83.49 vs 69.22 mGy; p = 0.019). Patient radiation exposure was significantly higher with the radiation-attenuating glove compared to the needle holder (8.43 vs 7.03 mSv; p = 0.027). Though radiation-attenuating gloves decreased hand radiation dose by 37%, this came at the price of a 3% increase in patient exposure. In contrast, the needle holder reduced exposure to both the surgeon's hand by 65% and the patient by 14%. Thus, a well-designed low-density needle holder could optimize radiation safety for both surgeon and patient.

Time Efficiency and Performance of Single-Use vs Reusable Cystoscopes: A Randomized Benchtop and Simulated Clinical Assessment.

Introduction: A flexible cystoscope is an indispensable tool for urologists, facilitating a variety of procedures in both the operating room and at bedside. Single-use cystoscopes offer benefits including accessibility and decreased burden for reprocessing. The aims of this study were to compare time efficiency and performance of single-use and reusable cystoscopes. Methods: Ten new Ambu® aScope™ 4 Cysto single-use and two Olympus CYF-5 reusable cystoscopes were compared in simulated bedside cystoscopy and benchtop testing. Ten urologists performed simulated cystoscopy using both cystoscopes in a randomized order. Times for supply-gathering, setup, cystoscopy, cleanup, and cumulative time were recorded, followed by a Likert feedback survey. For benchtop assessment, physical, optical, and functional specifications were assessed and compared between cystoscopes. Results: The single-use cystoscope demonstrated shorter supply-gathering, setup, cleanup, and cumulative times (824 vs 1231 seconds; p < 0.05) but a comparable cystoscopy time to the reusable cystoscope (202 vs 212 seconds; p = 0.32). The single-use cystoscope had a higher image resolution, but a narrower field of view. Upward deflection was greater for the single-use cystoscope (214.50° vs 199.45°; p < 0.01) but required greater force (2.5 × ). The working channel diameter and irrigation rate were greater in the reusable cystoscope. While the single-use cystoscope lacked tumor enhancing optical features, it had higher Likert scale scores for Time Efficiency and Overall Satisfaction. Conclusion: The single-use cystoscope demonstrates comparable benchtop performance and superior time efficiency compared to reusable cystoscopes. However, the reusable cystoscope has superior optical versatility and flow rate. Knowledge of these differences allows for optimal cystoscope selection based on procedure indication.

Does renal failure worsen radiation cystitis following radical prostatectomy?

OBJECTIVE: To investigate the impact of renal function on the risk, severity, and management of radiation cystitis in patients who underwent postoperative radiation therapy for prostate cancer. METHODS: Retrospective data was assessed from patients treated with adjuvant/salvage radiation therapy at a single academic institution between 2006 and 2020. The incidence, severity, and management of radiation cystitis were compared between three groups: CKD 0-2, CKD 3-4, and CKD 5. Associations of clinicopathologic factors with radiation cystitis were assessed in univariate and multivariate Cox regression models. RESULTS: A total of 110 patients who underwent radiation therapy following robot-assisted laparoscopic radical prostatectomy were included. The incidence of radiation cystitis following postoperative radiation therapy was 17% with a median presentation time of 34 months (interquartile range 16-65 months). The incidence of radiation cystitis was 100% in CKD 5 patients compared to 15% in CKD 0-2 and 17% in CKD 3-4 patients (p < 0.001). CKD 5 patients required more treatments, emergency department visits, and longer hospitalization times than CKD 0-4 patients (all p < 0.001). Multivariate analyses identified CKD 5 as the only significant factor associated with radiation cystitis (HR = 10.39, p = 0.026). CONCLUSION: End-stage renal failure is associated with the risk and severity of radiation cystitis in patients receiving postoperative radiation therapy. Knowledge of the potential morbidity of this complication in this population could guide physicians and patients as they evaluate risks and benefits prior to selecting adjuvant or salvage radiation therapy.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Intravascular Lymphoma with Progressive CNS Hemorrhage and Multiple Dissections.

INTRODUCTION: Intravascular lymphoma (IVL) is an uncommon and often fatal disease characterized by intraluminal proliferation of lymphomatous cells within blood vessels. Because of a heterogeneous clinical presentation and lack of sensitive diagnostic protocols, diagnosis of IVL is most often made at autopsy. However, with early diagnosis and appropriate chemotherapy, the prognosis is greatly improved and complete remission is possible. In order to broaden the possible presentations of IVL, we present a patient with an atypical manifestation of biopsy-proven intravascular large B-cell lymphoma who suffered dissections of both intracranial and extracranial arteries in addition to progressive intracranial hemorrhages. Case Report. A 47-year-old woman presented with unilateral paresthesias. She developed progressive multifocal infarcts and hemorrhage with dissections of both intracranial and extracranial arteries, resulting in coma. Brain biopsy revealed IVL. She received aggressive chemotherapy and remains in complete remission with good neurologic recovery. CONCLUSION: IVL is known to exert its pathology on small arteries and capillaries, but is not known to cause dissections of large vessels. The diagnosis should be considered in cases with unexplained arterial dissections and progressive strokes. Early diagnosis with appropriate laboratory screening and tissue confirmation by biopsy can lead to greatly improved outcomes.

Glioma Subclassifications and Their Clinical Significance.

The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. Recent advances in the molecular understanding of gliomas suggest some potential reasons for the failure of more targeted therapies in gliomas. Specifically, the histologic-based glioma classification is composed of multiple different molecular subtypes with distinct biology, natural history, and prognosis. As a result of these insights, the diagnosis and classification of gliomas have recently been updated by the World Health Organization. However, these changes and other novel observations regarding glioma biomarkers and subtypes highlight several clinical challenges. First, the field is faced with the difficulty of reinterpreting the results of prior studies and retrospective data using the new classifications to clarify prognostic assessments and treatment recommendations for patients. Second, the new classifications and insights require rethinking the design and stratification of future clinical trials. Last, these observations provide the essential framework for the development and testing of new specific targeted therapies for particular glioma subtypes. This review aims to summarize the current literature regarding glioma subclassifications and their clinical relevance in this evolving field.

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future.

OPINION STATEMENT: High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.

Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas.

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

Preadmission beta-blockers are associated with decreased incidence of neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Neurogenic stunned myocardium (NSM) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on disease course. The presumed cause is catecholamine surge at the time of aneurysm rupture. Beta-blockers, which reduce the impact of the catecholamine surge, may decrease the risk of developing NSM. METHODS: A chart review of 234 consecutive patients admitted to the Oregon Health and Science University Neurosurgery service between March 6, 2008 and June 23, 2010 with a diagnosis of aneurysmal SAH was performed. This group was further subdivided by patients who received echocardiograms on admission, by gender, and by the prehospital administration of ß-blockers. RESULTS: One hundred thirty of 234 patients had echocardiograms on or shortly after admission, and 18 of these developed NSM (13.8%). None of the 22 patients taking prehospital ß-blockers developed NSM. Using the Fisher exact test to compare the 2 groups, patients who were administered prehospital ß-blockers were significantly less likely to develop stunning compared to those who were not (P = .04). After correcting for other variables using multiple logistic regression analysis, the previous use of ß-blockers was still found to be significantly associated with a decreased incidence of NSM after SAH (P = .049). There was no significant difference in hospital length of stay, peribleed stroke, vasospasm, or death. Of the 18 patients with stunning, 15 were women, 5 of whom were on estrogen supplementation. The mean peak troponin elevation of women who developed NSM on estrogen supplementation was significantly higher than for those who were not (mean peak troponin 9.97 ± 2.01 mg/dL; P < .001). CONCLUSION: Prehospital ß-blockers are associated with decreased risk of developing NSM in patients with aSAH. Estrogen may play an additional role in shaping the degree of NSM in women.