Xanthine: Synthetic Strategy And Biological Activity

Xanthine and its derivatives belong to the class of purine alkaloids. They are natural bases holding nitrogen atoms within the molecular structure, and they have an effective pharmacological alteration in both animals and human beings. Substituted xanthine, theophylline/caffeine being prototype, is one of the derivatives which have shown prominent binding to adenosine receptors as agonist or antagonist. Various mechanistic approaches are involved in exerting bronchospasmolytic, neuroprotective, hypoglycemic, MAO modulatory, along cardiac effects. Mostly, xanthine derivatives reduce inflammation and bronchospasm in asthmatic conditions. Other therapeutics effects are in the management of cancer, Alzheimer's disease, vasoconstriction, and also possess excellent central nervous system-penetration ability; thus, they can also be used as stimulants and anti-depressants. Their actions are relatively very weak, but their pharmacological effects are also associated with snarl-up adenosine-mediated functions. An assortment of the biological profile of the xanthine scaffold attracted many research groups over the years to explore this nucleus vividly. The present review is aimed to cover every aspect of the xanthine moiety reported in the earlier years. This review covers all the major biological roles and various synthetic strategies adopted to synthesize xanthine moiety and its derivatives.

Recurrence of Primary Breast Lymphoma Presenting as Bilateral Vitreoretinal Lymphoma

<b><i>Purpose:</i></b> This report describes a case of relapsed primary breast lymphoma (PBL) presenting as vitreoretinal lymphoma (VRL). <b><i>Methods:</i></b> We describe the clinical and hematopathologic findings in a patient with relapsed PBL involving the vitreous of both eyes. <b><i>Results:</i></b> A 59-year-old woman was treated for PBL with systemic and intrathecal chemotherapy 5 years prior to presentation. Three years later, she presented to an outside clinic with blurred vision in both eyes and bilateral vitritis. She was referred to our clinic with concern for ocular lymphoma. On presentation, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/25 in the left eye with 3+ vitreous cells in the right eye and 2+ vitreous cells in the left eye. Vitreous biopsy of the right eye revealed CD5-negative/CD10-negative B-cell lymphoma cells on flow cytometry. She had no evidence of disease on brain MRI, lumbar puncture, bone marrow biopsy, or full-body CT scans. She was treated with a regimen of rituximab, methotrexate, procarbazine, and vincristine for central nervous system penetration as well as multiple intraocular injections of methotrexate and rituximab with improvement in vision and ocular inflammation bilaterally. <b><i>Conclusion:</i></b> Relapsed PBL can present as bilateral VRL.

Bilateral facial nerve palsies due to leptomeningeal progression of lung adenocarcinoma and response to osimertinib

A 39-year-old female Chinese non-smoker was diagnosed with epidermal growth factor receptor mutation-positive lung adenocarcinoma with cerebral metastases and commenced erlotinib. After 5 weeks, she presented with a 3-day history of severe bilateral facial weakness (House-Brackmann grade V/VI) and hypogeusia consistent with bilateral facial nerve palsies. MRI demonstrated new, symmetrical contrast-enhancing foci at the expected location of the facial nerves, consistent with leptomeningeal progression. Erlotinib was ceased and osimertinib was commenced. Facial nerve motor and sensory function began to improve within 1 week and by 2 weeks had returned to near normal. Review at 2 and 6 months demonstrated normal facial nerve function and progressive resolution of the facial nerve lesions on MRI. While rare, leptomeningeal malignancy may present as simultaneous bilateral facial nerve palsies. Osimertinib has superior central nervous system penetration and in this case was associated with rapid and sustained clinical and radiographical resolution of the facial nerve lesions.

Pseudomonal Meningoencephalitis With Ventriculitis Secondary to Bacteremia in a Burn Patient: A Novel Case

Burn patients with large burn surface area involvement are at increased risk of infection due to the presence of large wounds, multiple surgeries, prolonged intensive care unit admission, and immunosuppression. Pseudomonas aeruginosa is the most commonly isolated organism in this population. Even with frequent infections in the burn population, meningitis and encephalitis are rare, and ventriculitis is exceptional. We report the case of a 66-year-old woman who developed P. aeruginosa bacteremia during her hospital course, causing secondary meningoencephalitis with ventriculitis. She was admitted for partial- and full-thickness burns affecting the neck, chest, abdomen, upper medial arms, and bilateral anteromedial thighs for an estimated 20% total body surface area burn. She met sepsis criteria and broad-spectrum antimicrobial coverage was initiated. Magnetic resonance imaging of the brain, performed for altered mental status, revealed meningitis and ventriculitis. Cerebrospinal fluid analysis demonstrated findings consistent with bacterial meningitis, with cultures positive for P. aeruginosa. Serial neuroimaging with computerized tomography revealed new areas of ischemia concerning for septic emboli. In the presence of altered mental status and fever of unknown origin, workup should remain broad. Even in the presence of another source, it is important to keep an open mind for the rarer intracerebral infection as it requires different management, including urgent evaluation of antibiotic selection and dosing to ensure central nervous system penetration, and neurosurgical evaluation.

Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis

Purpose To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents. Methods We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different “SS reporting zones” were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (VD), and lipophilicity) and PD (values of binding affinity (Ki) and IC50 for serotonin reuptake transporter (SERT) and 5-HT2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index). Results Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large VD (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for VD/Ki SERT ratio (p = 0.05). Discussion Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

Factors affecting 48-hour methotrexate levels following high-dose methotrexate (HDMTX) in lymphoma.

e20033 Background: HDMTX is an important component of lymphoma therapy due to its central nervous system penetration. Although HDMTX can be safely administered to most patients, it can cause significant toxicity with those who have prolonged exposure to high plasma concentrations of MTX due to delayed elimination. Therefore, serum MTX concentration monitoring is still a standard approach for identifying patients at high risk of developing MTX toxicity. A majority of MTX is excreted within the first 48 hours of infusion. Higher MTX plasma concentrations at 48 hrs increase the likelihood of delayed MTX elimination. This study will assess baseline characteristics associated with high 48-hour MTX levels (≥ 1µM) which has been associated with increased risk of complications. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. Baseline demographics including age, gender, comorbidities, body surface area, BMI, weight and baseline chronic kidney disease (CKD) were recorded. Demographics, HDMTX dosing per protocol (3.5g/m2 vs 8g/m2), HDMTX adjusted by renal function (CrCl < 100), and ratio of MTX dose to BSA (MTX/BSA) were compared to 48 hour MTX levels. Analysis was performed in JMP 15. Results: 2553 cycles were of HDMTX were identified. There was a significant association of increasing age, (p = 0.039), male patients (p < 0.001), 8g/m2 dosing (p < 0.001), higher MTX dose (p < 0.001), MTX/BSA (p < 0.001), GFR by CKD-EPI (p < 0.001) and lower number of comorbidities (p < 0.001) with 48-hour MTX levels ≥1. There was no significant association of 48-hour MTX levels ≥1 and GFR by Cockcroft-Gault (p = 0.73), baseline CKD (p = 0.78), and renal adjusted HDMTX (p = 0.52). Multivariate analysis revealed significance for MTX/BSA, gender, BSA, GFR by CKDEPI (p < 0.001), and age (P = 0.0002). Conclusions: Hematologists should be aware that age, gender, GFR by CKD-EPI, and ratio of MTX dose to BSA are associated with elevated 48-hour MTX levels ≥1.

A Case of Ertapenem Neurotoxicity Resulting in Vocal Tremor and Altered Mentation in a Dialysis Dependent Liver Transplant Patient

Carbapenem agents are advanced derivatives of cephalosporins that are active against bacteria that produce extended spectrum beta lactamases (ESBL). These antibiotics are resistant to enzymatic cleavage, and have good central nervous system penetration. Given this fact, it is not surprising that these drugs have been reported to cause neurological side effects like seizures and encephalopathy. We report a case of a patient on hemodialytic support who had a notable change in mentation and vocal tremor. This was at first attributed to calcineurin toxicity, but after the finding of a normal tacrolimus level, ertapenem neurotoxicity was suspected. After discontinuation of the offending agent, the patient’s vocal tremor, cognition, and neurological function returned to baseline levels.