Riluzole use in presence of contraindications in adults affected by amyotrophic lateral sclerosis and its off-label use in other motor neuron diseases: Findings from an Italian multicentre study (the {CAESAR} project)

Background: This analysis describes the use of riluzole in amyotrophic lateral sclerosis (ALS) individuals with contraindications and off-label use for subjects with other motor neuron diseases (o-MND) in the Italian regions of Latium, Tuscany and Umbria.Methods: A cohort of adults with ALS prescribed with riluzole during the years 2016–2019 was enrolled from administrative healthcare databases, excluding subjects with o-MND in the preceding 5 years. Being affected by ALS for more than 5 years, presence of tracheostomy, renal or hepatic failure were considered as contraindications to the use of riluzole. A cohort of adults with o-MND was enrolled in 2016–2019 for whom off-label use of riluzole was retrieved up to 4 years, analysing over the time differences related to sex.Results: Among 206 ALS individuals prescribed with riluzole in Latium, 336 in Tuscany and 60 in Umbria, less than 1% were diagnosed with ALS for more than 5 years. Less than 2% were tracheotomised or affected by hepatic failure. Renal failure was documented for 1.9%, 2.7%, and 5.0% of ALS individuals in Latium, Tuscany and Umbria. The o-MND cohort comprised 264 subjects in Latium, 222 in Tuscany, and 66 in Umbria. Non-negligible off-label riluzole use was observed: 8.5%, 33.0%, and 4.2% in females, and 19.9%, 26.5% and 2.4% in males in Latium, Tuscany and Umbria.Discussion: Riluzole use in ALS individuals in the presence of contraindications is rare, with slightly higher numbers in presence of renal failure. Off-label use in o-MND was found to be non-negligible, with variations between sexes

Assessing disease activity of rheumatoid arthritis patients and drug-utilization patterns of biologic disease-modifying antirheumatic drugs in the Tuscany region, Italy

Introduction: The disease activity associated with the drug-utilization patterns of biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) is poorly investigated in real-world studies on rheumatoid arthritis (RA) patients. To investigate the relationship between biologic DMARD initiation/discontinuations in RA patients identified in the healthcare administrative databases of Tuscany and the Disease Activity Score 28 (DAS28) reported in the medical charts.Methods: This retrospective population-based study included RA’s first-ever biologic DMARD users of the Pisa University Hospital from 2014 to 2016. Patients were followed up until 31 December 2019. We evaluated the DAS28 recorded before (T0) and after (T1) the biologic DMARD initiation and before (TD0) and after (TD1) discontinuations. Patients were classified as “off-target” (DAS28 > 3.2) or “in-target” (DAS28 ≤ 3.2). We described the disease activity trends at initiation and discontinuation.Results: Ninety-five users were included (73 women, mean age 59.6). Among 70 patients (74%) with at least three DAS28 measures, 28 (40.0%) were off-target at T0 and 38 (54.3%) in-target at T1. Thirty-three (47%) patients had at least one discontinuation, among those with at least three DAS28 assessments. In the disease activity trend, disease stability or improvement was observed in 28 out of 37 (75.7%) patients at initiation and in 24 out of 37 (64.9%) at discontinuation.Discussion: Biologic DMARD discontinuations identified in the healthcare administrative databasese of Tuscany are frequently observed in situations of controlled RA disease. Further studies are warranted to confirm that these events can be used in studies using healthcare administrative databases as proxies of treatment effectiveness

Ruolo della glia enterica nella fisiopatologia dei disturbi motori intestinali in un modello di obesità indotto da dieta ipercalorica

L’obesità è una patologia multifattoriale, la quale, oltre ad essere caratterizzata da alterazioni della motilità intestinale, è associata ad insulino resistenza, incremento dello stress ossidativo, aumento dell’espressione dei markers di infiammazione e a un’aumentata permeabilità dell’epitelio intestinale. L’aumento della permeabilità intestinale comporta infatti un incremento del passaggio di batteri e altri antigeni presenti nel lume intestinale (es. lipopolisaccaride, LPS) attraverso la mucosa innescando così l’attivazione di processi immuno/infiammatori che determinano un notevole rimodellamento morfo-funzionale del compartimento neuromuscolare enterico, contribuendo alla genesi dei disturbi gastrointestinali. Studi recenti hanno dimostrato che le cellule gliali enteriche (EGCs), parte integrante del sistema nervoso enterico (SNE), svolgono un ruolo fondamentale nel regolare sia la permeabilità della barriera epiteliale che la motilità intestinale. Alterazioni della glia enterica possono determinare quindi risposte infiammatorie e alterazioni della permeabilità epiteliale che possono contribuire alla patogenesi della dismotilità intestinale associata all’obesità e alla diffusione del processo immuno-infiammatorio ad altri organi e apparati. Scopo dello studio: chiarire il ruolo della glia enterica nei processi immuno-infiammatori che conducono a una alterata permeabilità epiteliale con conseguente dismotilità intestinale e valutare l’eventuale coinvolgimento della glia nella regolazione delle funzioni neuromotorie enteriche di natura tachichininergica. Metodi In vivo: Topi maschi CB57BL/6 sono stati alimentati con una dieta ad alto contenuto di grassi (60% delle calorie derivanti da lipidi - high fat diet, HFD) per 8 settimane per riprodurre una situazione tipica dell’obesità. Animali di controllo sono stati alimentati con un dieta normocalorica (18% delle calorie derivanti da lipidi - standard diet, SD). Durante il periodo di trattamento, il peso corporeo è stato misurato settimanalmente. Al termine delle 8 settimane, gli animali sono stati sacrificati e i seguenti parametri sono stati esaminati: peso del grasso epididimale, livelli ematici di colesterolo, trigliceridi e glucosio. Il colon è stato isolato e utilizzato per l’allestimento di preparati di muscolatura liscia longitudinale, sui quali sono stati condotti studi funzionali mirati alla valutazione dell’attività contrattile tachichininergica neurogena e miogena. Inoltre, al fine di valutare la risposta infiammatoria enterica conseguente a una dieta HFD sono stati valuti i livelli di interleuchina (IL)-1β e IL-6 su campioni di colon isolati dai vari gruppi di trattamento. Su gli stessi campioni è stata valutata l’espressione della proteina tight junction occludina, al fine di corroborare l’ipotesi relativa ad un’aumentata permeabilità intestinale conseguente a un regime dietetico iperlipidico. Colture cellulari: la linea cellulare di glia enterica di ratto (EGC) è stata coltivata in opportuni mezzi di coltura. Le cellule gliali sono state trattate per 4 giorni con palmitato per mimare le condizioni di una dieta HFD e/o con lipopolisaccaride (LPS) nelle ultime 24 ore dell’esperimento. LPS è un componente della parete dei batteri gram negativi che può entrare in contatto con le cellule immunitarie della mucosa intestinale, in seguito a un aumento della permeabilità epiteliale intestinale. Al termine dell’esperimento le cellule sono state lisate per valutare i livelli di espressione di: recettori toll-like-4 (TLR-4), recettore responsabile del riconoscimento di LPS da parte delle cellule gliali; fosforilazione di JNK, fattore di trascrizione coinvolto nell’attivazione della trascrizione di geni codificanti per citochine infiammatorie. Per valutare il rilascio di IL-1β e sostanza P nei sovranatanti cellulari da parte dalle cellule gliali, sono stati utilizzati kit immunoenzimatici. Risultati I topi alimentati con HFD mostravano un aumento significativo del grasso epididimale, del peso corporeo e dei livelli plasmatici di glucosio, trigliceridi e colesterolo rispetto agli animali trattati con SD. Studi funzionali condotti su preparati di colon isolati da topi HFD mostravano un aumento significativo delle risposte tachichininergiche neurogene rispetto a topi SD, mentre le contrazioni miogene indotte da sostanza P esogena non risultavano modificate in maniera significativa. Inoltre, i tessuti colici prelevati da topi HFD e incubati con fluorocitrato (inibitore selettivo della glia enterica) all’interno dei bagni per organi isolati, hanno evidenziato una diminuzione delle contrazioni tachichininergiche neurogene, le quali risultavano simili a quelle osservate nei tessuti colici SD, suggerendo che la glia può rappresentare una fonte di sostanza P. Nei tessuti colici prelevati da animali alimentati con HFD, i livelli di IL-1β e Il-6 risultavano significativamente superiori rispetto a quelli osservati nei tessuti ottenuti da animali SD. L’espressione dell’occludina nel tessuto colico ottenuto da animali HFD risultava significativamente ridotta rispetto a quella osservata nei tessuti prelevati da topi SD. Per verificare il coinvolgimento della glia nelle alterazioni di natura infiammatoria e funzionale osservate nel tessuto intestinale in seguito ad assunzione di HFD sono stati condotti studi su cellule EGC. Nelle EGC trattate con palmitato, è stato osservato un aumento significativo dell’espressione dei TLR-4 e un aumento della fosforilazione di JNK, mentre non sono state osservate variazioni significative dei livelli di IL-1β e sostanza P nel sovranatante cellulare. Nelle EGC trattate con palmitato e LPS è stato osservato un aumento significativo dell’espressione di TLR-4 e della fosforilazione di JNK, e un incremento dei livelli di IL-1β e di sostanza P nel sovranatante cellulare. Conclusioni L’assunzione di una dieta HFD determina la comparsa di dismotilità intestinale, a cui si associa un incremento della permeabilità dell’epitelio intestinale e della risposta infiammatoria, presumibilmente causati da una incrementata attività della glia enterica. In questo contesto le cellule gliali sembrano contribuire alla modulazione della contrazione tachichininergica attraverso un aumento del rilascio di sostanza P

Tixagevimab + cilgavimab against SARS-CoV-2: the preclinical and clinical development and real-world evidence

IntroductionDirect-acting SARS-CoV-2 antiviral monoclonal antibodies have been an integral part of therapeutic strategies against COVID-19 pandemic. The monoclonal strategy was jeopardized by the emergence of new variants and resistant strains, making many monoclonal antibodies quickly obsolete. Nevertheless, a possible strategy consists in the use of antibody cocktails and the development of the cilgavimab + tixagevimab in combination is placed in this context.Areas coveredIn this review, we describe the development of the cilgavimab + tixagevimab cocktail, from pre-clinical to real-world evidence.Expert opinionThe pre-clinical and clinical development of cilgavimab + tixagevimab followed a similar path to that of the antibodies developed in the earlier stages of the pandemic. Both antibodies have been developed from convalescent plasma and have been shown to be effective in clinical trials in prophylaxis and in early therapy. This cocktail has found its position in therapy especially in immunocompromised subjects for whom vaccine prevention is not feasible. The cocktail strategy, together with a more stable pandemic situation, could ensure a certain longevity to the drug against resistance, especially when compared with that of other antibodies. Recently emerged Omicron sub-lineages have demonstrated the ability to escape this cocktail's activity and so the future of this treatment could be compromised

Lessons learnt from the preclinical discovery and development of ensitrelvir as a COVID-19 therapeutic option

IntroductionThe COVID-19 pandemic stimulated the development of several therapeutic tools with several degrees of success. Ensitrelvir, a protease inhibitor that blocks the replication of SARS-CoV-2, can reduce the viral load and the severity of symptoms in infected patients and become available for emergency use in Japan. Clinical trials showed a good tolerability profile although the potential for interactions with substrates, inhibitors, and inducers of CYP3A must be considered. The occurrence of resistance is also a matter of investigation.Areas coveredIn this article, the authors describe the development of ensitrelvir starting from the identification of the molecule to the pre-clinical and clinical trials up to the post-authorization phase.Expert opinionEnsitrelvir was developed in a late phase of the pandemic when the availability of patients that can be candidate to enter the clinical trial was limited with consequences for the possibility of assessing certain outcomes and for the robustness of results. Although the evidence about the benefits of ensitrelvir in COVID-19 is not questionable, the problems of interactions with other drugs, emerging resistant variants, the availability of alternative therapeutic options, costs, and accessibility will concur to its probable limited clinical use in the future

Communicating Drug Safety

Promoting safety of medications is imperative for optimal use, and the communication of the risk is entrusted to communicators. The communication of the risk of medicine requires peculiar expertise that is different from communications about its benefit. The identification of a risk related to a medicinal product is a dynamic process that involves the acquisition of information that progressively transforms into knowledge. In the initial stages of this process, the risk is often only potential but this uncertainty still requires caution. Uncertain risks are frequently matter of communication, and the magnitude of this uncertainty often drives the risk communication itself as the main subject. A message has to be tailored to the attitude and concerns of the target audience for achieving the best effects. Otherwise, uncertainties and hesitancies could persist even after the confirmation of the absence of a risk or could spread throughout media with consequent possible inappropriate use of drugs or therapeutic failure of medicines. In this regard, case studies such as measles vaccination and autism and the COVID-19 infodemic are paradigmatic examples. In risk communication about medicines, it is important to identify the subjects involved, define their roles (senders or receivers) and characteristics, to build the message and its content, and choosing the appropriate media for conveying the message. Several expertise is also required, including rhetoric, ethics, social sciences, and pharmacoepidemiology

Olfactory and gustatory impairments in COVID-19 patients: mechanism, clinical characteristics, drug interferences and role in early diagnosis

The main symptoms of SARS-CoV-2 infection include cough, dyspnoea and fever. However, many COVID-19 patients report also the early occurrence of smell (anosmia, hyposmia) and taste (ageusia, dysgeusia) impairments, suggesting the potential role of these manifestations in the timely diagnosis of COVID-19. This would be particularly important in the identification of asymptomatic and paucisymptomatic patients, and to support isolation and contagion chain tracking strategies. The pathophysiological mechanism underlying these symptoms is not clear. One of the most reliable hypotheses calls into play the interaction of SARS-CoV2 with the ACE2 enzyme, expressed in the oral mucosa and olfactory cavity. In this regard, drugs able to modulate the expression and activity of ACE2 could interfere with the identification of these symptoms, with uncertain impacts on the timely diagnosis and possibly the prognosis of COVID-19. Other commonly used drugs, with the potential of impairing chemosensory functions, could influence the detection of olfactory/gustatory symptoms as well. In this review, we provide a comprehensive description of the occurrence of taste and smell impairments in COVID-19 patients, discussing their diagnostic potential with a focus on possible interferences by medications

Exploring pharmacological approaches for managing cytokine storm associated with pneumonia and acute respiratory distress syndrome in COVID-19 patients

Sars-CoV-2 complications include pneumonia and acute respiratory distress syndrome (ARDS), which require intensive care unit admission. These conditions have rapidly overwhelmed healthcare systems, with detrimental effects on the quality of care and increased mortality. Social isolation strategies have been implemented worldwide with the aim of reducing hospital pressure. Among therapeutic strategies, the use of immunomodulating drugs, to improve prognosis, seems promising. Particularly, since pneumonia and ARDS are associated with a cytokine storm, drugs belonging to therapeutic classes as anti-IL-6, anti-TNF, and JAK inhibitors are currently studied. In this article, we discuss the potential advantages of the most promising pharmacological approaches

Preclinical discovery and development of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection: the rise and fall

Introduction The ongoing COVID19 pandemic represents an unprecedented opportunity to test the feasibility of monoclonal antibody (mAb) therapies against respiratory viruses. While many hurdles were easily predictable (e.g. time to develop, scalability, and economic sustainability), mAb cocktails (i.e. the combination of two mAbs) were finally deployed in 2021, one year after the beginning of the pandemic. Of them, the REGN-COV-2 cocktail was likely the most successful experience and contributed at saving lives at the time of the wave sustained by the Delta variant of concern (VOC). Areas Covered Herein, the authors review the preclinical and clinical history of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection. The authors furthermore provide the reader with their perspectives on this cocktail including its current place in the treatment armamentarium. Expert opinion Unfortunately, results from clinical trials highlighted a very limited efficacy in inpatients; furthermore, the current evidence with regards to its lack of effectiveness against the current dominant VOC (omicron) suggests a very limited use of these drugs in the future. In the authors' opinion, this story reminds us of the limitations of mAb therapies in pandemic settings, and of the inferiority of monoclonal versus polyclonal antibody-based therapeutics in such scenarios

The impact of COVID-19 “infodemic” on drug-utilization behaviors: implication for Pharmacovigilance

The COVID-19 pandemic that hit the world in 2020 triggered a massive dissemination of information (“infodemic”) about the disease channeled through the web and social media. This “infodemic” included also sensational and distorted information about drugs, which likely affected primarily opinion leaders and people particularly active on social media, and subsequently other peoples leading to inadequate choices by individual patients everywhere. In particular, for some drugs approved with other indications, namely chloroquine, hydroxychloroquine, NSAIDs, ACE inhibitors, angiotensin II receptor antagonists, favipiravir and umifenovir, information has spread that has led to a hazardous use. In this article, we analyzed the rationale behind the claim for use of these drugs in COVID-19, the communication about their effect on the disease, the consequences of this communication on people's behavior and the response of some influential regulatory authorities in an attempt to minimize the actual or potential risks arising from this behavior. Finally, we discussed the role of pharmacovigilance stakeholders in emergency management and possible strategies to be put in place to deal with other similar situations in the future