Background and objectives
Escitalopram (SCIT) is frequently prescribed to breastfeeding women. Available information on SCIT excretion into breast milk is based on heterogeneous and incomplete data. ...A population pharmacokinetic model that aimed to better characterize maternal and infant exposure to SCIT and its metabolite was developed.
Methods
The study population was composed of women treated by SCIT or racemic citalopram and enrolled in the multicenter prospective cohort study SSRI‐Breast Milk study (ClinicalTrial.gov NCT01796132). A joint structural model was first built for SCIT and S‐desmethylcitalopram (SDCIT) in plasma using NONMEM and the milk‐to‐plasma ratio (MPR) was estimated by adding the drug breast milk concentrations. The effect of different influential covariates was tested and the average drug exposure with variability through breastfeeding was predicted under various conditions by simulation.
Results
The study enrolled 33 patients treated with SCIT or racemic citalopram who provided 80 blood and 104 milk samples. Mean MPR for both parent drug and metabolite was 1.9. Increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT and +18% for SDCIT when fat amount doubles from 3.1 to 6.2 g/100 mL). Simulations suggested that an exclusively breastfed infant would ingest daily through breast milk 3.3% of the weight‐adjusted maternal SCIT dose on average.
Conclusion
The moderate between‐subject variability in milk concentration of SCIT and the limited exposure to escitalopram through breast milk observed provide reassurance for treated mothers of breastfed healthy infants.
We report the experimental generation of a broadband and flat mid-infrared supercontinuum in a silicon-germanium-on-silicon two-stage waveguide. Our particular design combines a short and narrow ...waveguide section for efficient supercontinuum generation, and an inverse tapered section that promotes the generation of two spectrally shifted dispersive waves along the propagation direction, leading to an overall broader and flatter supercontinuum. The experimentally generated supercontinuum extended from 2.4 to 5.5 μm, only limited by the long wavelength detection limit of our spectrum analyzer. Numerical simulations predict that the supercontinuum actually extends to 7.8 μm. We exploit the enhanced flatness of our supercontinuum for a proof-of-principle demonstration of free-space multi-species gas spectroscopy of water vapor and carbon dioxide.
Occipital nerve stimulation (ONS) is shown to be effective in treating various forms of headache. Most studies describe the treatment of occipital neuralgia (ON), but in many patients, the clinical ...description could also correspond to cervicogenic headache (CGH) or occipital migraine (OM). These different entities (ON, CGH, and OM) may be grouped together under the term occipital headaches.
To assess the efficacy of ONS to treat occipital headaches in a large series of patients with a long-term follow-up.
We performed a retrospective review of data on 60 patients with intractable occipital headaches treated with occipital nerve stimulation (ONS), who were referred to our center between October 2008 and October 2014. Details of pain evaluation, location, duration, cause and previous treatment were analyzed. Evaluations included the visual analog scale (VAS), the number of headache days per month (NHD), and the Medication Quantification Scale (MQS). Trials with transcutaneous electrical nerve stimulation (TENS-ONS) were performed and served as a guide for surgery indication (see Patients and Method section).
After one year of ONS, mean VAS had decreased from 8.4/10 to 2.8/10 (72.2% reduction p < 0.001), and 76% of patients had at least a 50% decrease in mean VAS score. The mean MQS score decreased from 18 to 8.8, corresponding to a reduction of pain medication by an average of 50%. Adverse events concerned 12 patients (20%). Six patients presented with electrode displacement or fracture (10%) and six patients presented with cases of infection (10%) associated with the pulse generator.
The results of this large series confirm that ONS is an effective treatment option for patients with intractable occipital headaches, but the frequency of complications remains quite high and must be taken into account in the surgical decision.
Acne in adult females is triggered mainly by hormones. Doxycycline is a reference treatment in acne. Spironolactone targets the androgen receptor of sebaceous glands and is prescribed off-label for ...female adult acne. This multicentre, controlled, randomized, double-blind prospective and parallel study assessed the efficacy of spironolactone compared with doxycycline in adult female acne. A total of 133 women with moderate acne were randomized to receive treatment with: (i) doxycycline and benzoyl peroxide for 3 months followed by a 3-month treatment with its placebo and benzoyl peroxide, or (ii) spironolactone and benzoyl peroxide for 6 months. Successfully treated patients continued with benzoyl peroxide or spironolactone alone for a further 6 months. Primary endpoints were treatment success at month 4 and month 6 with the AFAST score. At all visits, the ECLA score, lesion counts, local and systemic safety and quality of life were assessed. Spironolactone performed better at month 4 and showed a statistically significant better treatment success after 6 months than doxycycline (p = 0.007). Spironolactone was 1.37-times and 2.87-times more successful compared with doxycycline at respective time-points. AFAST and ECLA scores, as well as lesion counts always improved more with spironolactone. Patients' quality of life was better with spironolactone at month 4 and month 6. Spironolactone was very well tolerated. This is the first study to show that, in female adults with moderate acne, treatment with spironolactone is significantly more successful than doxycycline and very well tolerated.
Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of ...new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against
and
parasites. The compounds (
)-
, (
)-
, and
, having IC
values in nanomolar range against drug-resistant
strains, but also five other alkoxyamines, inducing the death of all adult worms of
in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants
for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.
Efficacy of imiquimod in the management of lentigo maligna Daude, Marie; Dinulescu, Monica; Nguyen, Jean‐Michel ...
Journal of the European Academy of Dermatology and Venereology,
September 2023, Letnik:
37, Številka:
9
Journal Article
Recenzirano
Background
Lentigo maligna (LM) is a melanocytic proliferation occurring on photo‐exposed skin that may progress to LM melanoma. Surgery is recommended as first‐line treatment. Excision margins of ...5–10 mm remain, without international consensus. Several studies have shown that imiquimod, an immunomodulator, induces LM regression. This study investigated the effect of imiquimod versus placebo in neoadjuvant settings.
Patients and Methods
We performed a prospective, randomized, multicentre, phase III clinical study. Patients were randomly assigned in 1:1 ratio to receive imiquimod or placebo for 4 weeks, followed by LM excision 4 weeks after the last application of imiquimod or placebo. The primary endpoint was extra‐lesional excision, with a 5 mm margin from the residual pigmentation after imiquimod or vehicle. Secondary endpoints included the gain on the surface removed between the two groups; number of revision surgeries to obtain extra‐lesional excisions; relapse‐free time; and number of complete remissions after treatment.
Results
A total of 283 patients participated in this study; 247 patients, 121 patients in the placebo group and 126 in the imiquimod group, accounted for the modified ITT population. The first extralesional extirpation was performed in 116 (92%) imiquimod patients and in 102 (84%) placebo patients; the difference was not significant (p = 0.0743). Regarding the surface of LM, imiquimod reduced the LM surface (4.6–3.1 cm2) significantly (p < 0.001) more compared to the placebo (3.9–4.1 cm2).
Conclusion
Imiquimod reduces the lentigo maligna surface after 1 month of treatment, without a higher risk of intralesional excision and with a positive aesthetic outcome.
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•Quantification of all SSRI antidepressants in human breast milk by HPLC–MS.•Method validation over a large concentration range including major metabolites.•Method application to ...patient samples from a clinical pharmacokinetic study.
A bioanalytical method by high performance liquid chromatography coupled to electrospray mass spectrometry (HPLC-ESI–MS), adapted from a previously published method in plasma, was validated in breast milk for the simultaneous quantification of all antidepressants belonging to the class of selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their major metabolites (desmethylcitalopram and norfluoxetine). Milk samples (250μl) first underwent protein precipitation followed by solid-phase extraction on a reversed phase/cation exchange sorbent. Analytes were thereafter separated on a XBridge C18 column (2.1mm×100mm; 3.5μm) using a mobile phase composed of ammonium acetate buffer (pH 8.1; 50mM) and acetonitrile in gradient mode. Detection was performed by a single quadrupole mass spectrometer running in selected ion monitoring in positive ionization mode. Method validation covered a wide concentration range of 2–500ng/ml for citalopram, desmethylcitalopram and paroxetine, 5–500ng/ml for sertraline, and 2–1000ng/ml for fluoxetine, norfluoxetine and fluvoxamine. Validation performances such as trueness (90.3–111.6%), repeatability (0.8–9.3%) and intermediate precision (0.9-9.5%) were in agreement with criteria from international guidelines and matrix effects for the analyte/internal standard ratios ranged from 92% to 110% (relative standard deviation <15%). Accuracy profiles (total error of trueness and precision) were lying within the limits of ±30% accepted in bioanalysis. Finally, the method was successfully applied to patient samples collected in a clinical pharmacokinetic study of nursing mothers taking an antidepressant treatment.
Background & aims
The recent approval of direct acting anti‐virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver ...carcinogenesis is debated. It has been hypothesized that changes in intrahepatic immune surveillance following viral cure could favour tumour growth.
This study aimed at characterizing the intrahepatic immune changes induced by HCV cure following DAA therapy.
Methods
Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after sustained virological response (SVR) to DAA therapy were included. A control group of untreated HCV‐infected patients with compensated cirrhosis was selected. RNA was extracted from tumoral and non‐tumoral tissues and analysed using the Nanostring Immuno‐Oncology‐360 panel. Immune cells were quantified by immunohistochemistry.
Results
Twenty patients were included: 10 patients with a DAA‐induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non‐tumoral tissue profiling showed down‐regulation of interferon‐related genes (including MX1, ISG15 and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra‐tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumours occurring in untreated patients.
Conclusion
In conclusion, removal of HCV infection after DAA‐based therapy results only in a down‐regulation of interferon‐stimulated genes in non‐tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favour HCC occurrence or recurrence after DAA‐induced SVR.
Prognostic biomarkers for patients with melanoma after lymph node resection are of clinical relevance and could thus enable the identification of patients who therefore would most benefit from ...adjuvant treatment. The aim of this work was to determine, using an in vitro model, whether immune‐related biomarkers, such as MHC‐class I and II, melanoma‐associated antigens, IDO1 and PD‐L1, could also be relevant to predict the risk of relapse of patients with stage III melanoma after lymph node resection. We established tumor cell lines from metastatic lymph nodes of 50 patients with melanoma. The expression of investigated biomarkers was determined on untreated and IFN‐γ treated melanoma cell lines using flow cytometry. Among the selected biomarkers, the IFN‐γ‐induced expression of PD‐L1 and IDO1 was associated with an increased risk of relapse (P = .0001 and P = .013, respectively) and was also associated with death for IDO1 (P = .0005). In the future, this immunologic signature could permit the identification of patients at higher risk of relapse and justifying an adjuvant treatment using immunotherapy.
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