Real-World Effectiveness of Calcitonin Gene-Related Peptide-Binding Monoclonal Antibodies for Migraine Prevention: A Systematic Review.

Background: Migraine is a neurological disease with a high incidence. The new anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) have demonstrated effectiveness in preventing episodic and chronic migraine. Objective: To collect evidence of the real-world effectiveness of anti-CGRP mAbs by assessing outcomes such as reduction in monthly migraine days (MMDs), reduction in monthly headache days (MHDs), and percentage of patients having a 50% reduction in MMDs. Data Sources: The PubMed database was searched for the period from inception to October 20, 2021. Study Selection and Data Extraction: Of interest for this review were studies that evaluated the real-world effectiveness of anti-CGRP mAbs in terms of MMDs and reduction in MHDs. The search terms included "migraine", "monthly migraine days", and various drug names. The data are reported in terms of patients' baseline characteristics and treatment effectiveness. Data Synthesis: A total of 46 studies were evaluated, of which 30 (enrolling a total of 4273 patients across 10 countries) were included in the systematic review. The greatest absolute reduction in MMD was from 20.4 at baseline to 10.7 after 3 months of treatment. After 6 months, the greatest absolute difference was 10, relative to baseline. The largest absolute reduction in MHD at 3 months was from 22 to 8, whereas at 6 months, the greatest absolute reduction in MHD was 13. The treatment could be considered clinically effective (≥ 50% reduction in MMDs) for 41% of patients at 3 months and about 44% of patients at 6 months. Conclusions: Despite substantial variability in baseline values, this review confirmed the effectiveness of anti-CGRP mAbs, which yielded important clinical reductions in both MMDs and MHDs.

Contexte: La migraine est une maladie neurologique à incidence élevée. Le nouvel anticorps monoclonal qui se lie au peptide lié au gène de la calcitonine (AcM anti-CGRP) a démontré son efficacité pour prévenir les migraines épisodiques et chroniques. Objectif: Recueillir des éléments probants concernant l'efficacité réelle des AcM anti-CGRP en évaluant des résultats comme la réduction du nombre de jours de migraine par mois (JMM), la réduction du nombre de jours de céphalées par mois (JCM) ainsi que le pourcentage de patients ayant une réduction de 50 % du nombre de JMM. Sources des données: La base de données PubMed a été utilisée pour mener une recherche pour la période allant du début jusqu'au 20 octobre 2021. Sélection des études et extraction des données: Les auteurs de la revue se sont intéressés aux études qui avaient évalué l'efficacité réelle des AcM anti-CGRP en termes de réduction du nombre de JMM et du nombre de JCM. Les termes de recherche comprenaient « migraine ¼, « jours de migraine par mois ¼ et divers noms de médicaments. Les données sont rapportées en termes de caractéristiques de base des patients et d'efficacité du traitement. Synthèse des données: Au total, 30 des 46 études répondant aux critères d'inclusion (comprenant un total de 4273 patients dans 10 pays) ont été retenues pour la revue systématique. La réduction absolue de JJM la plus importante était de 20,4 (la base de référence) à 10,7 après 3 mois de traitement. Après 6 mois, la différence absolue la plus importante était de 10 par rapport à la base de référence. La réduction absolue de JCM la plus importante à trois mois était de 22 à 8, alors qu'à 6 mois, la réduction absolue de JCM la plus importante était de 13. Le traitement pouvait être considéré comme cliniquement efficace (≥50 % de réduction de JMM) pour 41 % des patients à 3 mois et environ 44 % des patients à 6 mois. Conclusions: Malgré la variabilité importante des valeurs de la base de référence, cet examen confirme l'efficacité des AcM anti-CGRP, qui ont donné lieu à une réduction importante d'un point de vue clinique du nombre de JMM et de JCM.

A Systematic Review and a Meta-Analysis Comparing Prophylactic and Therapeutic Low Molecular Weight Heparins for Mortality Reduction in 32,688 COVID-19 Patients.

Background: Antithrombotic treatment, including low molecular weight heparin (LMWH) or unfractionated heparin (UFH), has been proposed as a potential therapy for coronavirus disease 2019 (COVID-19) to lower diffuse intravascular clotting activation. However, it is unclear whether prophylactic or therapeutic doses have similar efficacy in reducing mortality. Methods: We performed a systematic review (PROSPERO registration CRD42020179955) and meta-analysis including observational cohort studies and randomized controlled trials (RCT) evaluating the effectiveness of heparins (either LMWH, UFH, or fondaparinux) in COVID-19 patients. Heparin treatment was compared to no anticoagulation. A subgroup analysis on prophylactic or therapeutic doses compared to no anticoagulation was performed. Prophylactic dose was also compared to full dose anticoagulation. Primary endpoint was all-cause mortality. Secondary endpoints were major bleeding and length of hospital stay (LOS). Results: 33 studies (31 observational, 2 RCT) were included for a total overall population of 32,688 patients. Of these, 21,723 (66.5%) were on heparins. 31 studies reported data on all-cause mortality, showing that both prophylactic and full dose reduced mortality (pooled Hazard Ratio [HR] 0.63, 95% confidence interval [CI] 0.57-0.69 and HR 0.56, 95% CI 0.47-0.66, respectively). However, the full dose was associated with a higher risk of major bleeding (Odds Ratio [OR] 2.01, 95% CI 1.14-3.53) compared to prophylactic dose. Finally, LOS was evaluated in 3 studies; no difference was observed between patients with and without heparins (0.98, -3.87, 5.83 days). Conclusion: Heparin at both full and prophylactic dose is effective in reducing mortality in hospitalized COVID-19 patients, compared to no treatment. However, full dose was associated with an increased risk of bleeding. Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42020179955.

Consequences of the COVID-19 pandemic on the continuum of care in a cohort of people living with HIV followed in a single center of Northern Italy.

INTRODUCTION: During the COVID-19 pandemic, hospitals faced increasing pressure, where people living with HIV risked to either acquire SARS-CoV-2 and to interrupt the HIV continuum of care. METHODS: This is a retrospective, observational study. We compared the numbers of medical visits performed, antiretroviral drugs dispensed and the number of new HIV diagnosis and of hospitalizations in a cohort of people living with HIV (PLWH) followed by the Spedali Civili of Brescia between the bimester of the COVID-19 pandemic peak and the bimester of October-November 2019. Data were retrieved from administrative files and from paper and electronic clinical charts. Categorical variables were described using frequencies and percentages, while continuous variables were described using mean, median, and interquartile range (IQR) values. Means for continuous variables were compared using Student's t-tests and the Mann-Whitney test. Proportions for categorical variables were compared using the χ2 test. RESULTS: As of December 31st, 2019, a total of 3875 PLWH were followed in our clinic. Mean age was 51.4 ± 13 years old, where 28% were females and 18.8% non-Italian. Overall, 98.9% were on ART (n = 3834), 93% were viro-suppressed. A total of 1217 and 1162 patients had their visit scheduled at our out-patient HIV clinic during the two bimesters of 2019 and 2020, respectively. Comparing the two periods, we observed a raise of missed visits from 5 to 8% (p < 0.01), a reduction in the number of new HIV diagnosis from 6.4 in 2019 to 2.5 per month in 2020 (p = 0.01), a drop in ART dispensation and an increase of hospitalized HIV patients due to COVID-19. ART regimens including protease inhibitors (PIs) had a smaller average drop than ART not including PIs (16.6 vs 21.6%, p < 0.05). Whether this may be due to the perception of a possible efficacy of PIs on COVID19 is not known. CONCLUSIONS: Our experience highlights the importance of a resilient healthcare system and the need to implement new strategies in order to guarantee the continuum of HIV care even in the context of emergency.

Opportunity and challenges of nasal powders: Drug formulation and delivery.

In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate). Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations.

Parameters affecting the transscleral delivery of two positively charged proteins of comparable size.

Apart from molecular weight and net surface charge, there are other macromolecule-related factors that could, in principle, influence their diffusion across biological tissues, such as shape, conformability, water solubility and surface charge distribution. Lysozyme and cytochrome c, proteins with comparable molecular weight, isoelectric point and net surface charge in physiological conditions (approx. +7.8), are suitable model compounds for comparative studies, in particular to find out if other properties can have a role in the permeation across the sclera. The comparison between lysozyme and cytochrome c permeability was conducted by studying the permeation across the sclera and the choroid-Bruch's membrane and the diffusion across a hyaluronan gel-matrix. Melanin binding tests and the measurement of the electroosmosis flow during transscleral iontophoresis allowed for the evaluation of macromolecules affinity for the ocular tissues. Finally, anodal iontophoresis was applied to further confirm the interaction of the two proteins with the sclera. The data here collected show that two proteins with very similar MW, p Ka and charge can display very different diffusion properties across biological barriers. In particular, these differences can be attributed to a different interaction with specific components of ocular tissues: while the interaction with melanin and collagen fibers is apparently the same for the two molecules, a relevant difference was found in case of hyaluronic acid. Considering also literature evidences, the important parameters that can be responsible for this different affinity are molecular shape (spherical for cytochrome c vs prolate for lysozyme) and a combination of hydrophobic and electrostatic interactions that depends on the surface charge distribution. The interactions between sclera components and lysozyme are relatively strong and were not altered by the application of electric current.

In-vitro characterization of buccal iontophoresis: the case of sumatriptan succinate.

Buccal administration of sumatriptan succinate might be an interesting alternative to the present administration routes, due to its non-invasiveness and rapid onset of action, but because of its low permeability, a permeation enhancement strategy is required. The aim of this work was then to study, in-vitro, buccal iontophoresis of sumatriptan succinate. Permeation experiments were performed in-vitro across pig esophageal epithelium, a recently proposed model of human buccal mucosa, using vertical diffusion cells. The iontophoretic behavior of the tissue was characterized by measuring its isoelectric point (Na(+) transport number and the electroosmotic flow of acetaminophen determination) and by evaluating tissue integrity after current application. The results obtained confirm the usefulness of pig esophageal epithelium as an in-vitro model membrane for buccal drug delivery. The application of iontophoresis increased sumatriptan transport, proportionally to the current density applied, without tissue damage: electrotransport was the predominant mechanism. Integrating the results of the present work with literature data on the transport of other molecules across the buccal mucosa and across the skin, we can draw a general conclusion: the difference in passive transport across buccal mucosa and across the skin is influenced by permeant lipophilicity and by the penetration pathway. Finally, buccal iontophoretic administration of sumatriptan allows to administer 6mg of the drug in 1h, representing a promising alternative to the current administration routes.