The novel therapeutic application of ketamine in the context of abuse potential and liability: a critical issue for old and new drugs.

La ketamina \ue8 stata sviluppata come sostituta della fenciclidina e, come essa, si \ue8 dimostrata un potente \u201canestetico dissociativo\u201d. Tuttavia, i pazienti hanno spesso riportato \u201cemergence phenomena\u201d durante il risveglio (Ashton, 1998). La ketamina ha altri importanti usi medici. In particolare, alcuni studi clinici hanno mostrato che una sua singola infusione induce una rapida risposta antidepressiva nei soggetti con depressione maggiore (Berman et al., 2000). Tuttavia, la selezione di possibili farmaci ketamine-like dovrebbe anche basarsi su una appropriata valutazione dei suoi effetti indesiderati (Burgdorf et al., 2013). Pertanto, una precoce identificazione e caratterizzazione delle reazioni avverse da ketamina pu\uf2 essere utile al fine di definire i composti pi\uf9 appropriati da introdurre nella pratica clinica. Tra l\u2019altro, proprio quegli effetti che hanno limitato l'uso clinico della ketamina ne hanno favorito l'uso a scopo ricreativo (Morgan e Curran, 2011). Il sistema di farmacovigilanza (FV) svolge un ruolo importante per studiare il profilo di sicurezza dei farmaci. Inoltre, l'ultima legislazione europea di FV ha modificato la definizione di reazione avversa da farmaco (ADR) al fine di comprendere effetti nocivi e non voluti derivanti anche da abuso, errore terapeutico, esposizione professionale, misuso, overdose e uso off-label di un farmaco ("Sezione 7" della scheda di segnalazione italiana). L'obiettivo principale di questo progetto di ricerca era quello di capire come la FV potesse fornire informazioni sul profilo di sicurezza della ketamina come antidepressivo, sul suo abuso e sulla \u201cabuse liability\u201d dei farmaci. Dapprima si sono analizzati alcuni studi clinici sull'uso antidepressivo della ketamina; dei 14 studi selezionati sono state considerate le ADR, ma purtroppo non \ue8 stato possibile eseguire una revisione sistematica o meta-analisi. Con la seconda analisi si sono analizzate le schede contenuti nel database dell'OMS al fine di confrontare il profilo di sicurezza della ketamina se utilizzata a dosi sub-anestetiche o anestetiche. Nonostante i diversi dosaggi, in entrambi i gruppi le ADR sono risultate correlate a disturbi psichiatrici e disturbi del sistema nervoso. Per avere informazioni sull'abuso di ketamina, in primo luogo, \ue8 stato analizzato il database italiano di FV per valutare l'impatto della nuova definizione di ADR e si sono trovate solo 2 schede riferite all'abuso di ketamina; solo in un caso era stata selezionata la "Sezione 7". \uc8 stato poi analizzato il database dell\u2019OMS. Sono state estratte 202 schede e anche in questo caso si \ue8 rilevato che le reazioni pi\uf9 comuni riguardavano disturbi del sistema nervoso, disturbi psichiatrici e disturbi renali e urinari. In conclusione, questa ricerca ha dimostrato che, in letteratura non si trovano dati sufficienti riguardanti la sicurezza da ketamina come antidepressivo sia a breve che a lungo termine tanto che non \ue8 possibile eseguire revisioni sistematiche o meta-analisi. Tuttavia, l'analisi delle segnalazioni spontanee che \ue8 stata condotta ha confermato che anche basse dosi di ketamina provocano ADR che coinvolgono disturbi nervosi e psichiatrici. D'altra parte, la sorveglianza post-marketing non ha fornito molti risultati riguardanti l\u2019abuso di ketamina nonostante l'introduzione della nuova definizione di ADR. Nell'ambito della PV, sono necessarie alcune implementazioni al fine di poter fornire pi\uf9 supporto e informazioni utili sulla \u201cabuse liability\u201d di un farmaco.Ketamine was developed as a replacement for phencyclidine and like it ketamine was shown to be a potent \u201cdissociative anaesthetic\u201d. However, patients often reported \u2018emergence phenomena\u2019 during recovering from ketamine anaesthesia (Ashton, 1998). Ketamine has other important medical uses. In particular, some clinical studies showed that its single infusion induced a rapid antidepressant response in subjects with Major Depression Disorder (Berman et al., 2000). However, the selection of candidates should also be based on an appropriate evaluation of undesired ketamine-like effects (Burgdorf et al., 2013). Thus, an early identification and characterization of ketamine adverse drug reactions (ADRs) may be relevant, along with preclinical and clinical abuse liability studies as requested by regulatory agencies, in order to define the most appropriate compounds to be introduced in clinical practice. In fact, precisely those effects that limited the clinical use of ketamine made the drug appealing to recreational drug users and the its recreational use has increased over recent years in the world (Morgan and Curran, 2011). The pharmacovigilance (PV) system may play a role to study the safety profile of a drug. The monitoring of spontaneous suspected ADR reports represents a key component of the integrated systems of PV. Furthermore, the latest European PV legislation amended the definition of ADR in order to comprise noxious and unintended effects resulting also from abuse, medication errors, misuse, occupational exposure, off-label use and overdose (in the Italian reporting form: \u201cSection 7\u201d). The main objective of this research project was to study how the data collected from PV reports can provide information on the use of ketamine as an antidepressant as well as on its abuse. A critical analysis was then carried out on the information obtained regarding ketamine to determine the PV contribution might offer in the context of abuse liability. Clinical trials regarding the antidepressant use of ketamine were analysed. The ADRs reported in fourteen studies were considered, but, unfortunately, it was impossible to carry out a systematic review or meta-analysis. The second analysis considered the reports in the WHO database in order to compare the safety profile of ketamine when used at sub-anaesthetic or anaesthetic doses. Most of the ADRs in both groups were related to \u201cpsychiatric disorders\u201d, followed by \u201cnervous system disorders\u201d. To obtain information regarding ketamine abuse, two analyses were performed. First, the database of the Italian PV Network was analysed to assess the impact of the new definition of ADR. In database, there were 2 ADR reports referred to ketamine abuse. Only in one case \u201cSection 7\u201d was filled in. In the final analysis, the WHO database was analysed to detect the reports referring to ketamine abuse. 202 reports were extracted; the apparatus most commonly involved was nervous system disorders, followed by psychiatric disorders and renal/urinary disorders. In conclusion, the results of this research have shown that in literature there is not enough data on safety of ketamine as an antidepressant with the result that it is not possible to create a safety profile relating to either its short or long term use. However, the analysis of spontaneous reports confirmed that even low doses of ketamine cause ADRs involving nervous and psychiatric disorders. On the other hand, post-marketing surveillance based on spontaneous reporting has not revealed any significant new information concerning the abuse of ketamine. In fact, despite the new definition of ADR, reports of ketamine abuse in Italy and worldwide have not increased. In the area of PV, some further implementations are necessary in order to provide more support and more useful information concerning drug abuse liability

Normalizing Spontaneous Reports into MedDRA: some Experiments with MagiCoder

Text normalization into medical dictionaries is useful to support clinical task. A typical setting is Pharmacovigilance (PV). The manual detection of suspected adverse drug reactions (ADRs) in narrative reports is time consuming and Natural Language Processing (NLP) provides a concrete help to PV experts. In this paper we carry on experiments for testing performances of MagiCoder, an NLP application designed to extract MedDRA terms from narrative clinical text. Given a narrative description, MagiCoder proposes an automatic encoding. The pharmacologist reviews, (possibly) corrects, and then validates the solution. This drastically reduces the time needed for the validation of reports with respect to a completely manual encoding. In previous work we mainly tested MagiCoder performances on Italian written spontaneous reports. In this paper, we include some new features, change the experiment design, and carry on more tests about MagiCoder. Moreover, we do a change of language, moving to English documents. In particular, we tested MagiCoder on the CADEC dataset, a corpus of manually annotated posts about ADRs collected from social media

From narrative descriptions to MedDRA: automagically encoding adverse drug reactions

The collection of narrative spontaneous reports is an irreplaceable source for the prompt detection of suspected adverse drug reactions (ADRs). In such task qualified domain experts manually revise a huge amount of narrative descriptions and then encode texts according to MedDRA standard terminology. The manual annotation of narrative documents with medical terminology is a subtle and expensive task, since the number of reports is growing up day-by-day. Natural Language Processing (NLP) applications can support the work of people responsible for pharmacovigilance. Our objective is to develop NLP algorithms and tools for the detection of ADR clinical terminology. Efficient applications can concretely improve the quality of the experts\u2019 revisions. NLP software can quickly analyze narrative texts and offer an encoding (i.e., a list of MedDRA terms) that the expert has to revise and validate. MagiCoder, an NLP algorithm, is proposed for the automatic encoding of free-text descriptions into MedDRA terms. MagiCoder procedure is efficient in terms of computational complexity. We tested MagiCoder through several experiments. In the first one, we tested it on a large dataset of about 4500 manually revised reports, by performing an automated comparison between human and MagiCoder encoding. Moreover, we tested MagiCoder on a set of about 1800 reports, manually revised ex novo by some experts of the domain, who also compared automatic solutions with the gold reference standard. We also provide two initial experiments with reports written in English, giving a first evidence of the robustness of MagiCoder w.r.t. the change of the language. For the current base version of MagiCoder, we measured an average recall and precision of and , respectively. From a practical point of view, MagiCoder reduces the time required for encoding ADR reports. Pharmacologists have only to review and validate the MedDRA terms proposed by the application, instead of choosing the right terms among the 70\u202fK low level terms of MedDRA. Such improvement in the efficiency of pharmacologists\u2019 work has a relevant impact also on the quality of the subsequent data analysis. We developed MagiCoder for the Italian pharmacovigilance language. However, our proposal is based on a general approach, not depending on the considered language nor the term dictionary

Withdrawal Syndrome Following Discontinuation of 28 Antidepressants: Pharmacovigilance Analysis of 31,688 Reports from the WHO Spontaneous Reporting Database

Introduction: Evidence is lacking on withdrawal syndrome related to individual antidepressants and relevant risk factors for severe reactions. Objective: To ascertain whether antidepressants are associated with an increased reporting of withdrawal syndrome as compared with other medications, and to investigate risk factors for severe reactions. Methods: This is a case/non-case pharmacovigilance study, based on the VigiBase®, the WHO global database of individual case safety reports of suspected adverse drug reactions. We performed a disproportionality analysis of reports of antidepressant-related withdrawal syndrome (calculating reporting odds ratio [ROR] and Bayesian information component [IC]). We compared antidepressants to all other drugs, to buprenorphine (positive control), and to each other within each class of antidepressants (selective serotonin reuptake inhibitors [SSRIs], tricyclics and other antidepressants). Antidepressants with significant disproportionate reporting were ranked in terms of clinical priority. Serious versus non-serious reactions were compared. Results: There were 31,688 reports of antidepressant-related withdrawal syndrome were found. A disproportionate reporting was detected for 23 antidepressants. The estimated ROR for antidepressants altogether, compared to all other drugs, was 14.26 (95% CI 14.08-14.45), 17.01 for other antidepressants (95% CI 16.73-17.29), 13.65 for SSRIs (95% CI 13.41-13.90) and 2.8 for tricyclics (95% CI 2.59-3.02). Based on clinical priority ranking, the strongest disproportionate reporting was found for paroxetine, duloxetine, venlafaxine and desvenlafaxine, being comparable to buprenorphine. Withdrawal syndrome was reported as severe more often in males, adolescents, persons in polypharmacy, and with a longer antidepressant treatment duration (p < 0.05). Conclusions: Antidepressants are associated with an increased reporting of withdrawal syndrome compared with other drug classes. When prescribing and discontinuing antidepressants, clinicians should be aware of the potentially different proclivity of withdrawal syndrome across individual antidepressants, and the liability to experience more severe withdrawal symptoms in relation to specific patient characteristics

Liver injury due to amoxicillin vs. amoxicillin/clavulanate: a subgroupnalysis of a drug-induced liver injury case-control study in Italy

Several studies showed that amoxicillin plus clavulanic acid (co-amoxiclav) is one of the most common agents associated to serious Drug Induced Liver Injury (DILI). We estimated the risk of acute serious DILI associated with amoxicillin alone compared with co-amoxiclav, through a multicenter case-control study carried out in nine Italian hospitals from October 2010 to January 2014.Cases were adults, with a diagnosis of acute liver injury. Controls presented acute clinical disorders, not related to chronic conditions and not involving the liver. Adjusted Odds Ratio (ORs) with 95% CI were calculated initially with a bivariate and then multivariate analysis. We analysed 179 cases matched to 1770 controls. Seven cases were exposed to amoxicillin (adjusted OR 1.69, 95% CI 0.72-3.98) and 22 cases to co-amoxiclav (adjusted OR 3.00, 95% CI 1.76-5.40). Co-amoxiclav almost doubled the risk of serious acute liver injury compared to amoxicillin alone. The incidence of co-amoxiclav induced DILI is very low but the widespread use of this drug by the general population makes the risk clinically relevant. The often inappropriate prescription of antimicrobial agents, and in particular of co-amoxiclav, could expose a given patient to a life-threatening risk compared to a negligible clinical benefit

Sigh in patients with acute hypoxemic respiratory failure and acute respiratory distress syndrome: the PROTECTION pilot randomized clinical trial

Background: Sigh is a cyclic brief recruitment manoeuvre: previous physiological studies showed that its use could be an interesting addition to pressure support ventilation to improve lung elastance, decrease regional heterogeneity and increase release of surfactant. Research question: Is the clinical application of sigh during pressure support ventilation (PSV) feasible? Study design and methods: We conducted a multi-center non-inferiority randomized clinical trial on adult intubated patients with acute hypoxemic respiratory failure or acute respiratory distress syndrome undergoing PSV. Patients were randomized to the No Sigh group and treated by PSV alone, or to the Sigh group, treated by PSV plus sigh (increase of airway pressure to 30 cmH2Ofor 3 seconds once per minute) until day 28 or death or successful spontaneous breathing trial. The primary endpoint of the study was feasibility, assessed as non-inferiority (5% tolerance) in the proportion of patients failing assisted ventilation. Secondary outcomes included safety, physiological parameters in the first week from randomization, 28-day mortality and ventilator-free days. Results: Two-hundred fifty-eight patients (31% women; median age 65 [54-75] years) were enrolled. In the Sigh group, 23% of patients failed to remain on assisted ventilation vs. 30% in the No Sigh group (absolute difference -7%, 95%CI -18% to 4%; p=0.015 for non-inferiority). Adverse events occurred in 12% vs. 13% in Sigh vs. No Sigh (p=0.852). Oxygenation was improved while tidal volume, respiratory rate and corrected minute ventilation were lower over the first 7 days from randomization in Sigh vs. No Sigh. There was no significant difference in terms of mortality (16% vs. 21%, p=0.342) and ventilator-free days (22 [7-26] vs. 22 [3-25] days, p=0.300) for Sigh vs. No Sigh. Interpretation: Among hypoxemic intubated ICU patients, application of sigh was feasible and without increased risk

Analisi critica dei dati prescrittivi italiani

Il capitolo presenta i dati di prescrizione italiana degli analgesici oppiodi discutendo il dato anche nel contesto legislativo e politic

INTERAZIONI FARMACOLOGICHE

Al termine dello studio di questo capitolo lo studente dovrebbe essere in grado di conoscere: la classificazione e le caratteristiche principali delle interazioni farmacologiche; i meccanismi alla base delle interazioni; le pi\uf9 rilevanti interazioni tra farmaci, tra farmaci e prodotti erboristici o integratori alimentari, tra farmaci ed alimenti; le conseguenze cliniche delle interazioni

Farmacosorveglianza

Il capitolo fornisce gli elementi essenziali riguardanti la farmacosorveglianza. Dopo brevi cenni storici vengono definiti gli obiettivi della farmacosorveglianza, classificate e descritte le principali reazioni avverse da farmaci, illustrati i sistemi di sorveglianza con particolare riferimento alla segnalazione delle reazioni avverse

Lo strano colore della lingua di Giulia

Giulia \ue8 una bimba di 3 anni in buona salute con in anamnesi un episodio di sindrome di Kawasaki avvenuto all\u2019et\ue0 di un anno e risoltosi in breve tempo. Nei primi anni di vita non ha mai sofferto di patologie respiratorie o infezioni all\u2019orecchio, ma poco dopo l\u2019inizio dell'asilo ecco la prima otite! La bambina viene vista dal pediatra che diagnostica un\u2019otite media acuta. Viene cos\uec posta in monoterapia con amoxicillina per bocca al dosaggio di 3 ml/3 volte al giorno per 10 giorni. In concomitanza viene somministrato un antidismicrobico intestinale. Dopo 8 giorni dalla prima somministrazione la pediatra rivede la bimba per un controllo e in quell\u2019occasione riscontra un\u2019anomala condizione della lingua: essa ha una colorazione scura, \ue8 patinata posteriormente ed \ue8 pi\uf9 chiara anteriormente con aspetto villoso, senza presenza di candidosi. La condizione permane anche nei giorni successivi e la mamma riferisce anche l\u2019insorgere di alitosi. Si richiede pertanto la consulenza di uno specialista dermatologo che formula la diagnosi di \u201clingua villosa nera\u201d. In accordo con la pediatra, si decide di sospendere l'antibiotico in uso, nonostante la reazione insorta non sia segnalata sul riassunto delle caratteristiche del farmaco (RCP). Per risolvere completamente l\u2019otite, si imposta una terapia con azitromicina per bocca al dosaggio di 150 mg/die per 5 giorni. Per trattare invece la lingua, si consiglia di spazzolarla con uno spazzolino morbido al fine di velocizzare la regressione e di effettuare un'accurata igiene orale aiutandosi con l'utilizzo di collutori al bicarbonato in modo da alcalinizzare l'ambiente orale (i collutori con clorexidina avrebbero potuto, invece, aggravare la discromia). Dopo un mese dalla sospensione della terapia con amoxicillina, il problema della lingua di Giulia \ue8 definitivamente risolto