Neonatal Adaptation Issues After Maternal Exposure to Prescription Drugs: Withdrawal Syndromes and Residual Pharmacological Effects

Exposure to drugs during pregnancy has the potential to harm offspring. Teratogenic effects are the most feared adverse outcomes in newborns; however, a wide spectrum of less known, usually reversible and often acute, neonatal adverse events can also occur due to drug intake by mothers during pregnancy, particularly in close proximity to delivery. This narrative review is aimed at the description of drugs and drug classes for which licit maternal use in the predelivery period has been associated with neonatal non-teratogenic disorders. For each drug class, epidemiology, clinical features, biological mechanism and management of these adverse reactions have been discussed in detail. Although these adverse reactions have been described mainly for substances used illicitly for recreational purposes, several prescription drugs have also been involved; these include mainly psychotropic medications such as opioids, antidepressants, antiepileptics and antipsychotics. These effects can be partly explained by withdrawal syndromes (defined also as 'neonatal abstinence syndrome') caused by the delivery-related discontinuation of the drug disposition from the mother to the fetus, with symptoms that may include feeding disorders, tremors, irritability, hypotonia/hypertonia, vomiting and persistent crying, occurring a few hours to 1 month after delivery. Otherwise, neonatal neurological and behavioral effects can also be caused by a residual pharmacological effect due to an accumulation of the drug in the blood and tissues of the newborn, with various symptoms related to the toxic effects of the specific drug class, usually developing a few hours after birth. With few exceptions, validated protocols for the assessment and management of withdrawal or residual pharmacological effects of these drugs in neonates are often lacking or incomplete. Spontaneous reporting of these adverse reactions seems limited, although it might represent a useful tool for improving our knowledge about drug-induced neonatal syndromes

Is There a Risk of Lymphoma Associated With Anti-tumor Necrosis Factor Drugs in Patients With Inflammatory Bowel Disease? A Systematic Review of Observational Studies

Background: Inflammatory bowel diseases (IBDs) are generally not considered a risk factor for the development of lymphoma. When considering IBD treatments, there is good evidence supporting thiopurines (azathioprine, 6-mercaptopurine) as a risk factor for lymphoma. Conversely, the association between the use of anti-TNF agents and the development of lymphoma remains undetermined. In this systematic review, we analyzed the evidence coming from observational studies supporting an association between the use of anti-TNF drugs and lymphoma in patients with IBDs.Methods: This systematic review was performed according with MOOSE and PRISMA statements. We searched observational studies conducted on IBD patients, using MEDLINE, EMBASE, and Google Scholar, published in English language, within the period ranging from January 1st, 1999 to June 30th, 2018. An assessment of the methodologic shortcomings of selected studies was performed as well.Results: Fourteen studies met the eligibility criteria and were included in the review. Only four studies found a significant association of anti-TNF drug with lymphoma or groups of cancers including lymphoma. However, the methodologic shortcomings of all the included studies made their results unreliable, irrespectively of whether their findings supported an association or not.Conclusions: Current evidence from observational studies does not allow excluding or confirming an association of the exposure to anti-TNF treatments with lymphoma in IBD patients

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

Neonatal adaptation issues after maternal exposure to prescription drugs: withdrawal syndromes and residual pharmacological effects

Exposure to drugs during pregnancy can harm the offspring, causing or teratogenic effects, which are the most feared adverse effects in newborns, or a wide range of less known adverse effects, generally reversible and often acute, that can occur when the mother takes drugs during pregnancy, especially in close proximity to delivery. This thesis aims to describe drugs and drug classes for which licit maternal use in the pre-delivery has been associated with neonatal not teratogenic disorders. Epidemiology, clinical features, biological mechanism and management of these adverse reactions have been thoroughly discussed for each drug class. These adverse reactions were mainly described for substances used illicitly for recreational purposes, but many prescription drugs were also involved, including psychotropic medications, such as opiates, antidepressants, antipsychotics and anti-epileptics. These effects may be partly explained by withdrawal symptoms (also known as 'neonatal withdrawal syndrome') caused by the related suspension of delivery of drugs available from mother to fetus, with symptoms that may include feeding disorders, tremors, irritability, hypotonia / hypertonia, vomiting and persistent crying, occurring a few hours to 1 month after delivery. Otherwise, neonatal neurological and behavioral effects can be caused by a residual pharmacological effect due to an accumulation of the drug in the blood and tissues of the newborn, with various symptoms related to the toxic effects of the specific drug class, usually develop a few hours after birth. With few exceptions, validated protocols for the assessment and management of withdrawal or residual pharmacological effects of these medications in neonates are often lacking or incomplete. Spontaneous reporting of these adverse reactions seem limited, although it could be a useful tool to improve our understanding of drug-induced neonatal syndromes

ExPloring efficAcy, safeTy, and adHerence oF dIsease-modifyiNg antirheumatic Drugs through trajEctoRy model: the PATHFINDER study

Objectives: To test algorithms to select rheumatoid arthritis (RA) patients from the Tuscan healthcare administrative database (THAD). To identify and characterize trajectories and to investigate the relationship with the disease activity. Methods: The PATHFINDER study is a retrospective population-based study conducted on THAD (EUPAS29263). Three analyses were performed during this Ph.D. program. In the validation analysis, patients accessing the Rheumatology ward of Pisa University Hospital were extracted from THAD and the related medical charts represented the reference. The reference group included first-ever users of bDMARDs between 2014 and 2016 (index date) with at least a specialist visit. We tested four algorithms combining information on RA co-payment exemption codes, discharge record RA codes and emergency department access RA codes. We estimated sensitivity, specificity, positive and negative predicted values (PPV and NPV) with 95% confidence interval (95%CI). In the drug-utilization analysis, we included RA patients identified by the best performing algorithm. We observed users for 3 years or until death, neoplasia, or pregnancy. We evaluated adherence quarterly, through the Medication Possession Ratio. Firstly, we identified adherence trajectories; then, we focused on the most populated trajectory to distinguish the related sub-trajectories. In the effectiveness analysis, we extracted information on drug supplies from THAD and disease activity from medical charts. We measured discontinuations as the result of the coverage of each bDMARD dispensation based on DDD and the number of doses supplied plus a grace period amounting to 60 days and 30 days in the main and sensitivity analysis, respectively. We assessed DAS28 before (T0), after (T1) the first bDMARD supply, and before (TD0), after (TD1) discontinuation. Results: In the validation analysis, among 277 reference patients, 103 had RA. The fourth algorithm identified 96 true RA patients, PPV 0.78 (95%CI 0.70-0.85), sensitivity 0.93 (95%CI 0.86-0.97), specificity 0.84 (95%CI 0.78-0.90), and NPV 0.95 (95%CI 0.91-0.98). In the drug-utilization analysis, among 935 patients we identified 49 fully-adherent users, 829 continuous users, and 57 early-discontinuing users. Significant differences were observed among the index drugs. Three sub-trajectories were identified: continuous-steady users (556), continuous-alternate users (207), and continuous-declining users (66). No relevant differences emerged at the baseline. In the effectiveness analysis, 33 users had at least 1 discontinuation and 3 DAS28 assessments recorded. At T0, 28 patients had DAS28 >3.2 and 13 had DAS28 ≤3.2. At T1, 28 patients showed DAS28 >3.2, while 38 patients DAS28 ≤3.2. In the subgroup of RA first-ever bDMARD users with at least one discontinuation, a significant distribution of DAS28 >3.2 was observed at T1. Users continuing treatment displayed most frequently a DAS28 ≤3.2. Overall, 91 discontinuations were estimated and 38 displayed a DAS28 ≤3.2 at TD0. Out of 37 discontinuations with DAS28 recorded both at TD0 and at TD1, 27 showed no improvement. Conclusions: In conclusion, we identified the algorithm combining RA co-payment exemption code AND RA discharge record OR RA ED access record as the best performing. The majority of first-ever bDMARD users had a continuous adherence behavior. Disease control was achieved in half of RA patients starting bDMARDs, supporting treatment interruption

Authors’ response: Inhibiting IL-6 in COVID-19: we are not sure that sgp130(fc) can affect only the trans-signaling receptor pathway of IL-6

We appreciate the letter by Honore et al. and agree that a selective pharmacological approach is more rational than unspecific/non-selective medications. With regard to interleukin-6 (IL-6) targeting, we believe that current research, including the sgp130(fc) development, is rightly going towards this direction. Nevertheless, we wish to point out some considerations. Firstly, owing to the need of identifying promptly approaches for managing the COVID-19-related acute respiratory distress syndrome (ARDS), our article focused on drugs currently approved for other therapeutic indications, where they target cytokines involved in the COVID-19 inflammatory storm [1]. Secondly, we are well aware that IL-6 acts through both transmembrane IL-6 receptors (tmIL-6R; mainly regenerative or anti-inflammatory functions) and soluble IL-6 receptors (sIL-6R; trans-signaling pathway with pro-inflammatory actions). However, this anti-inflammatory/pro-inflammatory balance of the IL-6 receptor axis can be affected by several variables, such as proteases, other cytokines, concomitant drugs, genetic factors (up/down-regulation of tmIL-6R, sIL-6R, and gp130 expression), with relevant consequences on IL-6 signaling [5]. In this context, a specific/personalized therapeutic approach could be a good option, but it might be more suitable for chronic than acute conditions, such as the COVID-19-related ARDS. Moreover, even though IL-6 trans-signaling can be inhibited selectively, some detrimental conditions resulting from IL-6 blockade, such as serum increments of liver transaminases, lipids, cholesterol, and C-reactive protein, may still occur [6]. Thirdly, current evidence on the benefit of blocking the IL-6 pathway in COVID-19-related ARDS is encouraging. For instance, in a case series, 100 COVID-19 patients with ARDS displayed a prompt improvement after tocilizumab administration, in the setting of both intensive care (74%) and non-intensive care (65%) [7]. We agree with Honore et al. that sgp130(fc) could be a promising therapeutic approach. However, this novel biological drug exerts its inhibiting action on the IL-6 trans-signaling in a dose-dependent manner, and in an in vivo model, when administered at high dosage, it was shown to interfere also with the classical signaling pathway of tmIL-6R [8]. Thus, additional studies are required to identify the most appropriate anti-inflammatory dose of sgp130(fc) that could allow to achieve optimal benefits in the management of hyperinflammation associated with COVID-19-related ARDS. In conclusion, adequate clinical trials are required to assess whether a more favorable risk/benefit profile is associated with the inhibition of IL-6 trans-signaling, as compared with the overall blockade of IL-6 receptor pathways. While waiting for such evidence, we must continue to rely on currently available pharmacological approaches

The usefulness of listening social media for pharmacovigilance purposes: a systematic review

Introduction: Social media mining could be a possible strategy to retrieve drug safety information. The mining of social media is a complex process under progressive evolution, falling into three broad categories: listening (safety data reporting), engaging (follow-up), and broadcasting (risk communication). This systematic review is aimed at evaluating the usefulness and quality of proto-signals by social media listening. Areas covered: In this systematic search, performed according to MOOSE and PRISMA statements, we selected studies, published in MEDLINE, EMBASE, and Google Scholar until 31 December 2017, that listened at least one social media to identify proto-adverse drug events and proto-signals. Expert opinion: The selected 38 studies identified serious and unexpected proto-adverse drug events characterized by poorer information quality as compared with spontaneous reporting databases. This feature allows rarely the evaluation of causal relationships. Proto-signals identified by social media listening had the potential of anticipating pre-specified known signals in only six studies. Moreover, the personal perception of patients reported in social media could be used to implement effective risk communication strategies. However, signal detection in social media cannot be currently recommended for routine pharmacovigilance, due to logistic and technical issues

Is There a Risk of Lymphoma Associated With Anti-tumor Necrosis Factor Drugs in Patients With Inflammatory Bowel Disease? A Systematic Review of Observational Studies

Background: Inflammatory bowel diseases (IBDs) are generally not considered a risk factor for the development of lymphoma. When considering IBD treatments, there is good evidence supporting thiopurines (azathioprine, 6-mercaptopurine) as a risk factor for lymphoma. Conversely, the association between the use of anti-TNF agents and the development of lymphoma remains undetermined. In this systematic review, we analyzed the evidence coming from observational studies supporting an association between the use of anti-TNF drugs and lymphoma in patients with IBDs. Methods: This systematic review was performed according with MOOSE and PRISMA statements. We searched observational studies conducted on IBD patients, using MEDLINE, EMBASE, and Google Scholar, published in English language, within the period ranging from January 1st, 1999 to June 30th, 2018. An assessment of the methodologic shortcomings of selected studies was performed as well. Results: Fourteen studies met the eligibility criteria and were included in the review. Only four studies found a significant association of anti-TNF drug with lymphoma or groups of cancers including lymphoma. However, the methodologic shortcomings of all the included studies made their results unreliable, irrespectively of whether their findings supported an association or not. Conclusions: Current evidence from observational studies does not allow excluding or confirming an association of the exposure to anti-TNF treatments with lymphoma in IBD patients

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

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