Reply to Davison, G. Comment on "Huijghebaert et al. Does Trypsin Oral Spray (Viruprotect®/ColdZyme®) Protect against COVID-19 and Common Colds or Induce Mutation? Caveats in Medical Device Regulations in the European Union. Int. J. Environ. Res. Public Health 2021, 18, 5066".

We have read the comment from Davison with great interest [...].

COVID-19 and antiepileptic drugs: an approach to guide practices when nirmatrelvir/ritonavir is co-prescribed.

Management and dose adjustment are a major concern for clinicians in the absence of specific clinical outcome data for patients on antiepileptic drugs (AEDs), in the event of short-term (5 days) nirmatrelvir/ritonavir co-exposure. Therefore, in this report, we identified drugs that require dose adjustment because of drug-drug interactions (DDIs) between nirmatrelvir/ritonavir and AEDs. We hereby used four databases (Micromedex Drug Interaction, Liverpool Drug Interaction Group for COVID-19 Therapies, Medscape Drug Interaction Checker, and Lexicomp Drug Interactions) and DDI-Predictor.In the light of applying the DDI-Predictor, for carbamazepine, clobazam, oxcarbazepine, eslicarbazepine, phenytoin, phenobarbital, pentobarbital, rufinamide, and valproate as CYP3A4 inducers, we recommend that a dose adjustment of short-term nirmatrelvir/ritonavir as a substrate (victim) drug would be more appropriate instead of these AEDs to avoid impending DDI-related threats in patients with epilepsy.

Ways to Improve Insights into Clindamycin Pharmacology and Pharmacokinetics Tailored to Practice.

Given the increase in bacterial resistance and the decrease in the development of new antibiotics, the appropriate use of old antimicrobials has become even more compulsory. Clindamycin is a lincosamide antibiotic approved for adults and children as a drug of choice for systemic treatment of staphylococcal, streptococcal, and gram-positive anaerobic bacterial infections. Because of its profile and high bioavailability, it is commonly used as part of an oral multimodal alternative for prolonged parenteral antibiotic regimens, e.g., to treat bone and joint or prosthesis-related infections. Clindamycin is also frequently used for (surgical) prophylaxis in the event of beta-lactam allergy. Special populations (pediatrics, pregnant women) have altered cytochrome P450 (CYP)3A4 activity. As clindamycin is metabolized by the CYP3A4/5 enzymes to bioactive N-demethyl and sulfoxide metabolites, knowledge of the potential relevance of the drug's metabolites and disposition in special populations is of interest. Furthermore, drug-drug interactions derived from CYP3A4 inducers and inhibitors, and the data on the impact of the disease state on the CYP system, are still limited. This narrative review provides a detailed survey of the currently available literature on pharmacology and pharmacokinetics and identifies knowledge gaps (special patient population, drug-drug, and drug-disease interactions) to describe a research strategy for precision medicine.

Does Trypsin Oral Spray (Viruprotect®/ColdZyme®) Protect against COVID-19 and Common Colds or Induce Mutation? Caveats in Medical Device Regulations in the European Union.

BACKGROUND: nasal or oral sprays are often marketed as medical devices (MDs) in the European Union to prevent common cold (CC), with ColdZyme®/Viruprotect® (trypsin/glycerol) mouth spray claiming to prevent colds and the COVID-19 virus from infecting host cells and to shorten/reduce CC symptoms as an example. We analyzed the published (pre)-clinical evidence. METHODS: preclinical: comparison of in vitro tests with validated host cell models to determine viral infectivity. Clinical: efficacy, proportion of users protected against virus (compared with non-users) and safety associated with trypsin/glycerol. RESULTS: preclinical data showed that exogenous trypsin enhances SARS-CoV-2 infectivity and syncytia formation in host models, while culture passages in trypsin presence induce spike protein mutants. The manufacturer claims >98% SARS-CoV-2 deactivation, although clinically irrelevant as based on a tryptic viral digest, inserting trypsin inactivation before host cells exposure. Efficacy and safety were not adequately addressed in clinical studies or leaflets (no COVID-19 data). Protection was obtained among 9-39% of users, comparable to or lower than placebo-treated or non-users. Several potential safety risks (tissue digestion, bronchoconstriction) were identified. CONCLUSIONS: the current European MD regulations may result in insufficient exploration of (pre)clinical proof of action. Exogenous trypsin exposure even raises concerns (higher SARS-CoV-2 infectivity, mutations), whereas its clinical protective performance against respiratory viruses as published remains poor and substandard.

Vaccine Willingness and Impact of the COVID-19 Pandemic on Women's Perinatal Experiences and Practices-A Multinational, Cross-Sectional Study Covering the First Wave of the Pandemic.

The COVID-19 pandemic may be of particular concern for pregnant and breastfeeding women. We aimed to explore their beliefs about the coronavirus and COVID-19 vaccine willingness and to assess the impact of the pandemic on perinatal experiences and practices. A multinational, cross-sectional, web-based study was performed in six European countries between April and July 2020. The anonymous survey was promoted via social media. In total, 16,063 women participated (including 6661 pregnant and 9402 breastfeeding women). Most responses were collected from Belgium (44%), Norway (18%) and the Netherlands (16%), followed by Switzerland (11%), Ireland (10%) and the UK (3%). Despite differences between countries, COVID-19 vaccine hesitancy was identified among 40-50% of the respondents at the end of the first wave of the pandemic and was higher among pregnant women. Education level and employment status were associated with vaccine hesitancy. The first wave had an adverse impact on pregnancy experiences and disrupted access to health services and breastfeeding support for many women. In the future, access to health care and support should be maintained at all times. Evidence-based and tailored information on COVID-19 vaccines should also be provided to pregnant and breastfeeding women to avoid unfounded concerns about the vaccines and to support shared decision making in this population.

SARS-CoV-2 Infections and Impact of the COVID-19 Pandemic in Pregnancy and Breastfeeding: Results from an Observational Study in Primary Care in Belgium.

COVID-19 also affects pregnant and breastfeeding women. Hence, clinicians and policymakers require reliable evidence on COVID-19 epidemiology and consequences in this population. We aimed to assess the susceptibility of pregnant women to SARS-CoV-2 and women's perceived impact of the pandemic on their breastfeeding practices, medical counseling and social support. We performed a cross-sectional study using an online survey in primary care in Belgium. Pregnant and breastfeeding women and women who breastfed in the preceding four weeks were eligible to participate. The survey was distributed through social media in April 2020. In total, 6470 women participated (i.e., 2647 pregnant and 3823 breastfeeding women). Overall, 0.3% of all respondents reported to have tested positive for SARS-CoV-2, not indicating a higher susceptibility of pregnant women to contracting COVID-19. More than 90% refuted that the pandemic affected their breastfeeding practices, nor indicated that the coronavirus was responsible for breastfeeding cessation. Half of the women even considered giving longer breastmilk because of the coronavirus. In contrast, women's medical counseling and social support were negatively affected by the lockdown. Women without previous breastfeeding experience and in the early postpartum period experienced a higher burden in terms of reduced medical counseling and support. In the future, more consideration and alternative supportive measures such as tele-visits by midwives or perinatal organizations are required for these women.