RESUMO
HSV-2 antiviral resistance mainly occurs in immunocompromised patients and especially in HIV-positive individuals receiving long-term antiviral treatment. Those situations can be challenging as few alternatives are available for HSV infection management. To describe clinical and virological significance of two novel potential HSV-2 resistance mutations after treating an obese patient with a pseudotumoral genital HSV-related lesion. Consecutive different antiviral treatments were used: valacyclovir (VACV) then foscarnet (FOS) then topical cidofovir (CDV) and finally imiquimod. Under VACV, genotypic resistance testing revealed a novel mutation within viral thymidine kinase (TK, gene UL23) not previously reported but probably accounting for antiviral resistance: W89G, similar to W88R mutation reported in HSV-1 TK, known to be associated with ACV resistance for HSV-1. Under FOS, while initial mutations were still present, a second genotypic resistance testing performed on persisting lesions showed a novel mutation within viral DNA polymerase (DNA pol, gene UL30): C625R. All three antivirals used in this case are small molecules and pharmacokinetics of VACV, FOS, and CDV have not been evaluated in animals and there are very few studies in human. As small molecules are poorly bound to proteins and distribution volume is increased in obese patients, there is risk of underdosage. This mechanism is suspected to be involved in emergence of resistance mutation and further data is needed to adapt, closely to patient profile, antiviral dosage. This report describes a chronic HSV-2 genital lesion, with resistance to current antivirals and novel mutations within viral TK and DNA pol which may confer antiviral resistance.
Assuntos
Herpes Simples , Herpesvirus Humano 2 , Aciclovir/farmacologia , Aciclovir/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Cidofovir/uso terapêutico , DNA Polimerase Dirigida por DNA/genética , Farmacorresistência Viral/genética , Foscarnet/uso terapêutico , Genitália , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 2/genética , Humanos , Imiquimode/uso terapêutico , Mutação , Obesidade , Timidina Quinase/genética , Timidina Quinase/uso terapêutico , Valaciclovir/uso terapêuticoRESUMO
Data regarding elderly melanoma patients treated with anti-PD-1 or anti-CTLA-4 antibodies are in favor of tolerability outcomes that are similar to those of younger counterparts. However, there are very few studies focusing on elderly patients receiving nivolumab combined with ipilimumab (NIVO + IPI). Here, we ask what are the current prescribing patterns of NIVO + IPI in the very elderly population and analyze the tolerance profile. This French multicenter retrospective study was conducted on 60 melanoma patients aged 80 years and older treated with NIVO + IPI between January 2011 and June 2022. The mean age at first NIVO + IPI administration was 83.7 years (range: 79.3-93.3 years). Fifty-five patients (92%) were in good general condition and lived at home. Two dosing regimens were used: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (NIVO1 + IPI3) in 27 patients (45%) and NIVO 3 mg/kg + IPI 1 mg/kg Q3W (NIVO3 + IPI1) in 33 patients (55%). NIVO + IPI was a first-line treatment in 39 patients (65%). The global prevalence of immune-related adverse events was 63% (38/60), with 27% (16/60) being of grade 3 or higher. Grade ≥ 3 adverse events were less frequent in patients treated with NIVO3 + IPI1 compared with those treated with NIVO1 + IPI3 (12% versus 44%, p = 0.04). In conclusion, the prescribing patterns of NIVO + IPI in very elderly patients are heterogeneous in terms of the dosing regimen and line of treatment. The safety profile of NIVO + IPI is reassuring; whether or not the low-dose regimen NIVO3 + IPI1 should be preferred over NIVO1 + IPI3 in patients aged 80 years or older remains an open question.
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Background: Immune checkpoint inhibitors (ICIs) have been a major advance in treating non-small-cell lung cancer (NSCLC). Programmed cell death protein-1/programmed death-ligand 1 blockade enhances immune function, mediating anti-tumor activity, yet causing immune-related adverse events (irAEs). We investigated the prognostic role of Grade 3−4 irAEs on overall survival (OS). Methods: This observational study recruited advanced NSCLC patients who received ICIs at Bichat-Claude Bernard University Hospital and in a community hospital, Saint-Joseph Foundation (Paris), between 1 January 2016 and 31 December 2019. Immunotherapy as a single-agent or double-drug combination was applied in the first and later lines. Univariable and multivariable analyses were instrumental in evaluating the prognostic impact of irAEs. Results: Overall, 201 consecutive ICI-treated patients were enrolled. High-grade irAEs (Grades 3−4) occurred in 36 patients (17.9%), including 11 (30.5%) cases of pneumonitis, 8 (22.2%) of colitis, 4 (11.1%) hepatic, 3 (8.3%) dermatological, 2 (5.5%) neurological events, and 2 cases (5.5%) of poly-arthralgia. The median OS was 10.4 ± 1.36 months (95% CI:7.7−13.1), being significantly higher in patients with high-grade irAEs than those without, 27.8 months vs. 8.1 months, respectively (HR = 2.5; p < 0.0001). Multivariable analysis revealed an independent association between high-grade irAEs and longer OS (HR = 0.29, 95% CI: 0.2−0.6, p < 0.0001). Conclusions: Our real-life study confirms that high-grade irAEs predict longer OS in advanced NSCLC.
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Glucocorticoids (GCs) are amongst the most widely used and effective treatments to control inflammatory and autoimmune diseases. In obese subjects, drug dosing adjusted by body weight is problematic, all the more so as patients are at higher risk of GC metabolic side effects. We propose here to describe the determinants of drug pharmacokinetics (PK) in obese subjects and GC pharmacology, and to identify the existing PK studies that may help discussing the best size descriptor for GC dosing in obese subjects. A clinician and a pharmacist screened PubMed using the MeSH Terms: "glucocorticoids" OR "steroidal agents" AND "pharmacokinetics" AND "obesity" OR "overweight". The search was limited to the publications written in English language and to those performed in humans. A systematic search using the MeSH terms was performed until August 31st, 2017. Only three such PK studies have been published so far that compare dexamethasone, prednisolone and methylprednisolone in obese and normal weight subjects. The studies concur that GC partially distribute in the excess of body weight and that adjustment by total body weight (TBW) or by body weight (BW) excess would increase the initial plasma GC concentration after a loading dose and would thus be inappropriate. Contradictory results are observed regarding GC exposure or clearance according to the GC studied. Behind this overwhelming lack of conclusive evidence for adjusting GC by body weight, further PK studies are clearly needed for guiding their dosing. Furthermore, studies demonstrated an increased sensibility to GC, even when GC exposure was reduced, suggesting that adjustment by body weight may not only be unnecessary but also dangerous.
Assuntos
Peso Corporal/fisiologia , Cálculos da Dosagem de Medicamento , Glucocorticoides/administração & dosagem , Obesidade/tratamento farmacológico , Índice de Massa Corporal , Relação Dose-Resposta a Droga , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacocinética , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/metabolismoRESUMO
An important issue in the follow-up of patients with bariatric surgery remains to determine whether their therapeutic management should be different after surgery. In this article, we first reviewed all pharmacokinetic studies involving at least four subjects who underwent the Roux-en-Y gastric bypass (RYGB) bariatric surgery. Twenty-five publications were selected and, overall, 25 drugs were studied. Drug solubility and permeability parameters for each drug were defined using different parameters or classifications. Increased rates of oral drug absorption were predominantly observed. Conversely, drug exposure differed from one drug to another. Considering the galenic formulation and the Biopharmaceutics Classification System (BCS) class may help the prediction of oral drug exposure outcome after RYGB. We propose a strategy aiming to guide prescription and drug monitoring in patients with RYGB. But further research is clearly needed due to the unique characteristics of the bariatric population. Priority should be given to drugs that do not have clinical or biological surrogates for dose adaptation.
Assuntos
Derivação Gástrica , Obesidade Mórbida/cirurgia , Farmacocinética , Administração Oral , Monitoramento de Medicamentos/métodos , Humanos , Absorção Intestinal , Obesidade Mórbida/metabolismo , Permeabilidade , Preparações Farmacêuticas/administração & dosagem , Cuidados Pós-Operatórios/métodos , Período Pós-OperatórioRESUMO
BACKGROUND: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB) is required for optimizing their use in this growing population. OBJECTIVE: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma PKs between patients with RYGB and their controls. SETTINGS: University hospital, Lariboisière Hospital, Paris. METHODS: Thirty milligrams of morphine as a sustained-release formulation was orally administered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine, morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period were determined by a validated method using liquid chromatography mass spectrometry in tandem. Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit. RESULTS: Morphine oral area under the curve (for time 0-12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ± 38.8 nmol.hr/L for RYGB group and control group, respectively, P = .71), morphine at maximal concentration, metabolites oral area under the curve (for time 0-12 hr), and other PK parameters were similar between groups. After drug administration, mean drowsiness was superior in RYGB group. Mean respiratory rate and oxygen saturation were similar in both groups. CONCLUSION: No dose adjustment seems to be needed for sustained release morphine when prescribed to RYGB patients.