Hiccups in Parkinson's disease: an analysis of cases reported in the European pharmacovigilance database and a review of the literature.

BACKGROUND: Some reports have suggested an association between dopamine agonists and hiccups, involuntary contractions that merit full clinical attention because they can be very debilitating. Many drugs frequently used to treat hiccups are formally contraindicated in Parkinson's disease due to their liability to worsen motor symptoms, making the treatment of hiccups problematic in this disease. The objective of the present study was to analyze all spontaneous reports of hiccups from the European Pharmacovigilance Database in patients with Parkinson's disease and/or on dopaminergic drugs. Finally, we sought to identify evidence-based recommendations on the management of hiccups in Parkinson's disease. METHODS: We searched for all reports of hiccups in the European Pharmacovigilance Database (EudraVigilance) and calculated proportional reporting ratios for dopamine agonists and hiccups. We reviewed the literature on Parkinson's disease, dopamine agonists, and hiccups, searching for specific treatment recommendations for hiccups in this disease. RESULTS: Both rotigotine and pramipexole fulfilled the criteria to generate a safety signal. We found 32 and 13 cases of hiccups associated with dopamine agonists in EudraVigilance and the literature, respectively. There were no specific recommendations for the management of hiccups in Parkinson's disease in the clinical guidelines consulted. CONCLUSIONS: We have found evidence that rotigotine and pramipexole are associated with the appearance of hiccups and that this adverse reaction occurs predominantly in males. Given the scarce information available, specific recommendations are needed in clinical guidelines for the adequate management of hiccups in Parkinson's disease.

Analyzing the potential environmental impact of NIOSH list of hazardous drugs (group 2).

For the first time, several pharmaceuticals have been defined as priority substances in the new proposal of the revision of the Water Framework Directive (WFD). Consequently, environmental quality standards have been determined for several drugs. This is the case with the antiepileptic carbamazepine, which is considered as hazardous in healthcare settings by The National Institute for Occupational Safety and Health (NIOSH). This organism considers as such drugs that have shown teratogenicity, carcinogenicity, genotoxicity or other developmental, reproductive, or organ toxicity at low doses in studies with animals or humans. This study has been focused on the non-carcinogenic drugs classified in group 2, and their presence in the environment. This group contains many different therapeutic agents such as antineoplastics, psychoactive drugs, immunosuppressants and antivirals, among others. Of the 116 drugs included in the list, 26 have been found in aquatic environmental matrices. Certain drugs have received most attention (e.g., the antiepileptic carbamazepine, progesterone and the antidepressant paroxetine) while others completely lack environmental monitoring. Carbamazepine, fluconazole, paroxetine and warfarin have been found in invertebrates' tissues, whereas carbamazepine, oxazepam and paroxetine have been found in fish tissues. The main aim of the NIOSH's hazardous drug list is to inform healthcare professionals about adequate protection measures to prevent occupational exposure to these pharmaceuticals. However, this list contains useful information for other professionals and researchers such as environmental scientists. The paucity of relevant environmental data of certain hazardous pharmaceuticals might be important to help in the prioritization of compounds that may demand further research.

Hazardous drugs (NIOSH's list-group 1) in healthcare settings: Also a hazard for the environment?

Healthcare workers can be exposed to dangerous drugs during their daily practice. The National Institute for Occupational Safety and Health (NIOSH) considers "hazardous drugs" as those that had shown one or more of the following characteristic in studies with animals, humans or in vitro systems: carcinogenicity, teratogenicity or other toxicity for development, reproductive toxicity, organ toxicity at low doses, or genotoxicity. In the actual list (draft list 2020), drugs classified in group 1 are those with carcinogenic effects. Moreover, the global human and veterinary cancer is expected to grow, so antineoplastic drug consumption may consequently grow, leading to an increase of anticancer pharmaceuticals in the environment. Not all drugs pertaining to group 1 can be classified as "antineoplastic" or "cytostatic". Since most of the research on environment presence and ecotoxicological effects of pharmaceuticals has been focused on this therapeutic class, other carcinogenic drugs belonging to different therapeutic groups may have been omitted in previous studies. In this study we aim to review the presence in the environment of the hazardous drugs (NIOSH group 1) and their possible environmental impact. Of the 90 drugs considered, there is evidence of presence in the environment for 19. Drugs with more studies reporting positive detections are: the antibiotic chloramphenicol (55), the alkylating agents cyclophosphamide (39) and ifosfamide (30), and the estrogen receptor modulator tamoxifen (18). Although the original purpose of the NIOSH list and related documents is to provide guidance to healthcare professionals in order to adequately protect them from the hazards posed by these drugs in healthcare settings, we believe they can be useful for environmentalists too. Absence of data regarding the potential of environmental risk of certain hazardous drugs might tell us which drugs ought to be prioritized in the future.

Drugs used during the COVID-19 first wave in Vitoria-Gasteiz (Spain) and their presence in the environment.

The city of Vitoria-Gasteiz was one of the probable first entrances of the SARS-CoV2 in Spain, one of the worst affected countries in the world during the first COVID 19 wave. Driven by the urgency of the situation, multiple drugs with antiviral activity were used off label. Sadly, most of these treatments were of little or no benefit and thus, the number of patients suffering from COVID-19 attended in intensive care units (ICUs) multiplied. After being administered to patients, a variable proportion of these drugs reach the environment where they may have detrimental effects, although this aspect is usually ignored by healthcare professionals. In this study we measured the patterns of hospital drug use in the city of Vitoria-Gasteiz (Spain) during the first COVID-19 wave pandemic, focusing on those with antiviral activity and those used in the ICUs. Subsequently, we measured concentrations of selected drugs in the city's wastewater treatment plant influent and effluent and estimated the potential risk for the environment. The hospital use of certain antivirals and drugs used for sedo-analgesia were dramatically increased during the first wave (cisatracurium was multiplied by 25 and lopinavir/ritonavir by 20). A mean of 1.632 daily defined doses of hydroxychloroquine were used during the period of February-May 2020. In this study we report the first positive detection of hydroxychloroquine ever in the environment. We also show the second positive report of lopinavir. Low risk was estimated for hydroxychloroquine, lopinavir and ritonavir (Risk quotients (RQ) <1), and medium risk for azithromycin (RQ 0f 0.146).

Drug pollution & Sustainable Development Goals.

The United Nations set "The 2030 Agenda for Sustainable Development," which includes the Sustainable Development Goals (SDGs), a collection of 17 global goals designed to be a "blueprint to achieve a better and more sustainable future for all". Although only mentioned in one of the seventeen goals (goal 3), we argue that drugs in general, and growing drug pollution in particular, affects the SDGs in deeper, not readily apparent ways. So far, the emerging problem of drug pollution has not been sufficiently addressed. Here, we outline and discuss how drug pollution can affect SDGs and even threaten their achievement.

Antipsychotics as environmental pollutants: An underrated threat?

The heterogeneous class of what we nowadays call antipsychotics was born almost 70 years ago with the serendipitous discovery of chlorpromazine. Their utilization is constantly growing because they are used to treat a diverse group of diseases and patients across all age groups: schizophrenia, bipolar disease, depression, autism, attention deficit hyperactivity disorder, behavioural and psychological symptoms in dementia, among others. They possess a complex pharmacological profile, acting on multiple receptors: dopaminergic, serotoninergic, histaminergic, adrenergic, and cholinergic, leading scientists to call them "agents with rich pharmacology" or "dirty drugs". Serotonin, dopamine, acetylcholine, noradrenaline, histamine and their respective receptors are evolutionary ancient compounds, and as such, are found in many different living beings in the environment. Antipsychotics do not disappear once excreted by patient's urine or faeces and are transported to wastewater treatment plants. But as these plant's technology is not designed to eliminate drugs and their metabolites, a variable proportion of the administered dose ends up in the environment, where they have been found in almost every matrix: municipal wastewater, hospital sewage, rivers, lakes, sea and even drinking water. We believe that reported concentrations found in the environment might be high enough to exert significant effect to aquatic wildlife. Besides, recent studies suggest antipsychotics, among others, are very likely bioaccumulating through the web food. Crucially, psychotropics may provoke behavioural changes affecting populations' dynamics at lower concentrations. We believe that so far, antipsychotics have not received the attention they deserve with regards to drug pollution, and that their role as environmental pollutants has been underrated.