Combined isosorbide dinitrate and ibuprofen as a novel therapy for muscular dystrophies : evidence from Phase I studies in healthy volunteers

We designed two Phase I studies that assessed healthy volunteers in order to evaluate the safety and to optimize the dosing of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a nonsteroidal antiinflammatory drug. We designed these studies with the aim of designing a Phase II trial to evaluate the drugs' efficacy in patients affected by Duchenne muscular dystrophy. For the first trial, ISOFEN1, a single-dose, randomized-sequence, open-label, active control, three-treatment cross-over study, was aimed at comparing the pharmacokinetics of ibuprofen 200 mg and isosorbide dinitrate 20 mg when given alone and concomitantly. The pharmacokinetics of ibuprofen given alone versus ibuprofen given concomitantly with isosorbide dinitrate were similar, as documented by the lack of statistically significant differences in the main drug's pharmacokinetic parameters (time to maximal concentration [Tmax], maximal concentration [Cmax], area under the curve [AUC]0-t, and AUC0- 1e). Similarly, we found that the coadministration of ibuprofen did not significantly affect the pharmacokinetics of isosorbide dinitrate. No issues of safety were detected. The second trial, ISOFEN2, was a single-site, dose titration study that was designed to select the maximum tolerated dose for isosorbide dinitrate when coadministered with ibuprofen. Eighteen out of the 19 enrolled subjects tolerated the treatment well, and they completed the study at the highest dose of isosorbide dinitrate applied (80 mg/day). One subject voluntarily decided to reduce the dose of isosorbide dinitrate from 80 mg to 60 mg. The treatment-related adverse events recorded during the study were, for the large majority, episodes of headache that remitted spontaneously in 0.5-1 hour - a known side effect of isosorbide dinitrate. These studies demonstrate that the combination of isosorbide dinitrate and ibuprofen does not lead to pharmacokinetic interactions between the two drugs; they also demonstrate that the combination of isosorbide dinitrate and ibuprofen has optimal tolerability and safety profiles that are similar to those previously reported for isosorbide dinitrate and ibuprofen given alone

An evaluation of elvitegravir plus cobicistat plus tenofovir alafenamide plus emtricitabine as a single-tablet regimen for the treatment of HIV in children and adolescents

Introduction: Approximately 2.1 million of the estimated 36 million infected with HIV are children or adolescents. International guidelines for HIV-1 Infection suggest starting antiretrovirals (ARV) at the moment of diagnosis. Many factors limit the optimization of antiretroviral therapy in children and adolescents: lack of pediatric formulations, poor adherence, metabolic and pharmacokinetic changes associated withnormal child development and puberty. Areas covered: Three integrase inhibitors are approved by the US Food and Drug Administration and by European Medical Agency for children and adolescents with HIV-1 infection. Raltegravir is approved for children aged 4\ua0weeks to 18\ua0years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6\ua0years of age. This article evaluates E/C/FTC/TAF as a treatment option. Expert opinion: E/C/FTC/TAF was well tolerated, and the antiretroviral activity and tolerability data of this combination support the use in children and adolescents. However, the studies regarding E/C/FTC/TAF in children and adolescents are scant. Consequently, additional studies investigating its safety and efficacy in children are paramount

Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects : an Italian cohort

Background: Dolutegravir plus darunavir provide a high genetic barrier to HIV-1 resistance and are suitable for simple salvage regimens. Methods: All HIV-1-infected subjects treated with dolutegravir plus boosted darunavir dual therapy between March 2011 and September 2015 were included in an observational cohort. Data were collected at baseline and at weeks 4, 12, 24 and 48. Results: We enrolled 113 subjects. After week 24, one was lost at follow-up, one dropped out for grade 2 elevation of liver enzymes, one died from illicit drug abuse and one from cancer-related sepsis. The mean age was 51, 26.5% were female and 9.7% were non-Caucasian. Twenty had never experienced failure. A total of 99 had reverse-transcriptase (RT) mutations, 87 had protease inhibitor mutations and 12 had integrase strand transfer inhibitor (INSTI) mutations. Viraemic patients declined from baseline to week 24 from 43.4% to 6.2%, the remainder being due to high baseline viraemia or adherence issues. The proportion of subjects with viraemia 1\u201349 copies/ml remained at 20.4% while those in whom no virus was detected (NVD) increased from 36.3% to 73.5% by week 24. All the 47 subjects who had a 48-week follow-up had <50 copies/ml and 42 (89.4%) had NVD. 18 subjects had reduced sensitivity to darunavir (Stanford median score 15, range 15\u201340), but none rebounded, 6 having a 24-week and 7 a 48-week follow-up. The median variation in serum creatinine was -0.01 (range +0.2 to -0.21) mg/dl. Conclusions: This dual regimen provides a simple salvage regimen and proved safe and effective in this cohort

Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers : a randomized, open-label, 2-period, single-dose, crossover phase 1 study

BACKGROUND: The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interindividual and intraindividual variability. We documented previously that HIV patients taking RAL at 400 mg bid by chewing the tablets had significantly higher drug absorption and reduced pharmacokinetic variability than patients taking the drug by swallowing the tablets. This study extends our previous findings. METHODS: An open-label, 2-period crossover study compared the pharmacokinetics of 2 doses of RAL given at 400 mg every 12 hours (that mimics a bid administration) by swallowing with 1 dose of 800 mg (that mimics a qd administration) by chewing the tablets in 12 healthy volunteers. RAL plasma concentrations were measured by a chromatographic method coupled with mass spectrometry. RESULTS: Subjects taking RAL by chewing had significantly higher drug exposure (RAL area under the curve[AUC](0-24): 40722 \ub1 14843 versus 21753 \ub1 12229 ng \ub7 h/mL, P < 0.0001) and reduced pharmacokinetic variability compared with those taking the drug by swallowing the whole tablet, with no difference in the minimum RAL concentrations (RAL C(min): 36 \ub1 23 versus 43 \ub1 23 ng/mL, P = 0.298). Subjects taking RAL by chewing the tablets had significantly higher drug absorption and reduced pharmacokinetic variability compared with those taking the drug by swallowing. No differences were observed in the minimum RAL concentrations. CONCLUSIONS: RAL at 800 mg once daily by chewing the tablets may represent a novel therapeutic option for the treatment of HIV being associated with higher drug absorption, reduced pharmacokinetic variability, and potentially better compliance compared with patients swallowing the 400-mg bid intact tablets

Durability of dolutegravir plus boosted darunavir as salvage or simplification of salvage regimens in HIV-1 infected, highly treatment-experienced subjects

Background: Dolutegravir (DTG) plus boosted darunavir (bDRV) is a compact, adherence-friendly salvage regimen with the highest genetic barrier to HIV-1 resistance. Objective: Aim of the present study is to assess the long term (96-week) safety and efficacy of DTG + bDRV in a of multidrug-experienced HIV-1 infected patients, simplifying or building rescue regimens. Methods: All HIV-1-infected subjects from eleven Italian centers switched to DTG + bDRV between March 2014 and September 2015 were included and followed for minimum 96 weeks. Results: The cohort comprises 130 subjects, switched from 42 different, complex or at least twice-daily regimens, mainly for simplification (44.6%), viral failure (30.0%) or toxicity (16.6%). At baseline 118 had documented resistance to 1\u20135 antiretroviral classes and 12 lacked genotypic results either for historical reasons or for problems with primer annealing; 52 (40%) had uncontrolled viral replication, three above 500.000 copies/mL. At week 96 two showed 6550 HIV-1 RNA copies/mL, 23 had 1\u201349 copies/mL and 101 had no virus detected. The proportion of subjects presenting abnormal values at baseline significantly decreased for serum glucose, creatinine, AST, total cholesterol and triglycerides. Conclusions: These long-term data confirm the reliability of the two-drug regimen consisting of bDRV plus DTG in salvage settings in HIV-1 infection

Les coûts subjectifs de l’enquête ethnographique

L’enquête ethnographique implique toujours un engagement personnel et de longue durée du chercheur, et donc une socialisation minimale au milieu enquêté. Dans une enquête dans des associations, partis ou mouvements militants, dont un des enjeux est de produire de l’adhésion et de l’« enrôlement », la sur-socialisation au milieu enquêté est d’autant plus probable que l’affinité du chercheur avec la cause défendue est préalable au démarrage de l’enquête. À travers le récit du déroulement de l’enquête et des états psycho-moraux traversés au cours de celle-ci, sont ici donnés à voir tant les conditions rendant possibles l’adhésion et la loyauté militantes que les coûts subjectifs et éthiques liés à la rupture avec le terrain, constitutive de l’acte d’écriture.Field research always implies the personal and long-term commitment of the researcher, and thus a minimal socialization in the world investigated. In a research in activist movement, which goal is to produce commitment, these socialization can be very strong, especially when the researcher was still an activist in the starting up of the field work. Through the telling the story of progress of the research and psycho-moral states crossed during this one, are here given to see the conditions making possible the activist loyalty and the subjective and ethical costs connected to the break with the field, which is a necessity of the act of writing.Los costos subjetivos de la encuesta etnográfica. Investigar siendo militante en la asociación Droit Au Logement (DAL) a fines de los años 1990.La encuesta etnográfica implica un compromiso personal de duración larga del investigador; lo que significa una socialización mínima del medio estudiado. Investigar en los medios asociativos, de partidos o de movimientos sociales, medios en los cuales es obvio que el reto central es la búsqueda de la adhesión y del reclutamiento, con lleva una probabilidad muy elevada de enfatizar la socialización si además el investigador comparte la defensa de la causa desde le inicio de la encuesta. Apoyándose sobre el narración de la marcha de la investigación y de los estados « psico-morales » a travesados por ella, se da a ver las condiciones que permiten la adhesión y la lealtad militante a lo mismo que el costo subjetivo y ético vinculado con la ruptura con el campo que provoca el acto de escritura

Effectiveness of switching to darunavir/cobicistat in virologically-suppressed HIV-positive patients receiving ritonavir-boosted protease inhibitor-based regimen : the &quot;STORE&quot; Study

Objective: This study investigates the effectiveness and tolerability of switching to darunavir/cobicistat (DRV/c)-based antiretroviral regimen (ART) from a ritonavir-boosted protease inhibitor (PI/r)-based regimen in virologically suppressed human immunodeficiency virus (HIV)-positive patients. DRV trough values were also investigated. Setting: Prospective, multicenter, single-country, non-interventional, cohort study. Methods: This study included patients on a PI/r-based ART for at least twelve months having plasma HIV-1 RNA &lt;50 copies/mL for at least six months. Primary endpoint: HIV-1 RNA &lt;50 copies/mL at 48 \ub1 6 weeks from baseline. A secondary analysis was performed using the time to loss of virological response (TLOVR) algorithm. Biochemical parameters including DRV trough samples were collected as per clinical practice and measured using high-performance liquid chromatography. Results: Of 336 patients enrolled, 282 completed the study: 70.8% had plasma HIV-1 RNA &lt;50 copies/mL at 48 weeks; using the TLOVR algorithm, 82.7% maintained virological suppression. Virological failure (VF) was observed in 6 patients (1.8%). Adverse event (AE)-related discontinuations were 4.5%. After 48 weeks, we found a significant improvement in both triglycerides (median, 130.0 mg/dL to 113.5 mg/dL, p=0.0254) and HDL cholesterol (48 to 49 mg/dL, p&lt;0.0001) but no change in other biomarkers. DRV trough concentrations in 56 subjects showed a median value of 2862.5 (1469.5-4439.0) ng/mL, higher in females than in males (4221 ng/mL vs. 2634 ng/mL, p=0.046). Conclusions: In stable HIV-1 positive virologically suppressed patients, the switch to DRV/c-based ART was beneficial in terms of low rates of VF and AEs due to its high tolerability and improvement in triglycerides

Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post_treatment hospitalisation status

SARS-CoV-2 is causing an increasing number of deaths worldwide because no effective treatment is currently available. Remdesivir has shown in vitro activity against coronaviruses and is a possible antiviral treatment for SARS-CoV-2 infection. This prospective (compassionate), open-label study of remdesivir, which was conducted at Luigi Sacco Hospital, Milan, Italy, between February 23 and March 20, 2020, involved patients with SARS-CoV-2 pneumonia aged 6518 years undergoing mechanical ventilation or with an oxygen saturation level of 6494% in air or a National Early Warning Score 2 of 654. The primary outcome was the change in clinical status based on a 7-category ordinal scale (1 = not hospitalised, resuming normal daily activities; 7 = deceased). The 35 patients enrolled from February 23 to March 20, 2020, included 18 in intensive care unit (ICU), and 17 in our infectious diseases ward (IDW). The 10-day course of remdesivir was completed by 22 patients (63%) and discontinued by 13, of whom eight (22.8%) discontinued because of adverse events. The median follow-up was 39 days (IQR 25-44). At day 28, 14 (82.3%) patients from IDW were discharged, two were still hospitalized and one died (5.9%), whereas in ICU 6 (33.3%) were discharged, 8 (44.4%) patients died, three (16.7%) were still mechanically ventilated and one (5.6%) was improved but still hospitalized. Hypertransaminasemia and acute kidney injury were the most frequent severe adverse events observed (42.8% and 22.8% of the cases, respectively). Our data suggest that remdesivir can benefit patients with SARS-CoV-2 pneumonia hospitalised outside ICU where clinical outcome was better and adverse events are less frequently observed. Ongoing randomised controlled trials will clarify its real efficacy and safety, who to treat, and when