Therapie最新文献

Antibiotics are drugs widely used all around the world. Central nervous system adverse drug reactions (CNS ADRs) are mostly under-suspected with antibiotics. Nevertheless, these ADRs could lead to severe complications such as encephalopathy. To illustrate the clinical patterns of these off-target ADRs, we here present data from pharmacovigilance system, through different populations and points of view (worldwide, French population, vulnerable population and individual). These data could help clinicians to better know about CNS ADRs with antibiotics, to better identify risk factors and vulnerable patients and to highlight the importance to set up the right diagnostic explorations in the best timing to avoid complications. Clinicians should request a pharmacological opinion from pharmacologist (biologists and pharmacovigilance clinicians) in front of vulnerable population before or during antibiotics. Pharmacovigilance advice could help clinicians in the diagnosis and the management of an ADR. Therapeutic drug monitoring is particularly contributive to adjust doses of antibiotics administered in vulnerable patients. Pharmacovigilance advice and TDM are essential to perform personalized medicine, and contribute to the proper use of drugs.

Sensorineural hearing loss (SNHL) is the most common type of hearing loss. Causes include degenerative changes in the sensory hair cells, their synapses and/or the cochlear nerve. As human inner ear hair cells have no capacity for regeneration, their destruction is irreversible and leads to permanent hearing loss. SNHL can be genetically inherited or acquired through ageing, exposure to noise or ototoxic drugs. Ototoxicity generally refers to damage to the structures and functions of the inner ear following exposure to specific drugs. Ototoxicity can be multifactorial, causing damage to cochlear hair cells or cells with homeostatic functions that modulate cochlear hair cell function. Clinical strategies to limit ototoxicity include identifying patients at risk, monitoring drug concentrations, performing serial hearing assessments and switching to less ototoxic therapy. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using the PubMed® database. The search terms “ototoxicity”, “hearing loss” and “drugs” were combined. We included studies published between September 2013 and June 2023, and focused on medicines and drugs used in hospitals. The review highlighted a number of articles reporting the main drug classes potentially involved: namely, immunosuppressants, antimalarials, vaccines, antibiotics, antineoplastic agents, diuretics, nonsteroidal anti-inflammatory drugs and analgesics. The presumed ototoxic mechanisms were described, together with the therapeutic and preventive options developed over the last ten years.

Drug-induced kidney diseases represent a wide range of diseases that are responsible for a significant proportion of all acute kidney injuries and chronic kidney diseases. In the present review, we focused on drug-induced glomerular diseases, more precisely podocytopathies – minimal change diseases (MCD), focal segmental glomerulosclerosis (FSGS) – and membranous nephropathies (MN), from a physiological and a pharmacological point of view. The glomerular filtration barrier is composed of podocytes that form foot processes tightly connected and directly in contact with the basal membrane and surrounding capillaries. The common clinical feature of these diseases is represented by the loss of the ability of the filtration barrier to retain large proteins, leading to massive proteinuria and nephrotic syndrome. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), D-penicillamine, tiopronin, trace elements, bisphosphonate, and interferons have been historically associated with the occurrence of MCD, FSGS, and MN. In the last ten years, the development of new anti-cancer agents, including tyrosine kinase inhibitors and immune checkpoint inhibitors, and research into their renal adverse effects highlighted these issues and have improved our comprehension of these diseases.

Background

Drug-induced hyperglycemia and diabetes have negative and potentially serious health consequences but can often be unnoticed.

Methods

We reviewed the literature searching Medline database for articles addressing drug-induced hyperglycemia and diabetes up to January 31, 2023. We also selected drugs that could induce hyperglycemia or diabetes according official data from drug information databases Thériaque and Micromedex. For each selected drug or pharmacotherapeutic class, the mechanisms of action potentially involved were investigated. For drugs considered to be at risk of hyperglycemia or diabetes, disproportionality analyses were performed using data from the international pharmacovigilance database VigiBase. In order to detect new pharmacovigilance signals, additional disproportionality analyses were carried out for drug classes with more than 100 cases reported in VigiBase, but not found in the literature or official documents.

Results

The main drug classes found to cause hyperglycemia are glucocorticoids, HMG-coA reductase inhibitors, thiazide diuretics, beta-blockers, antipsychotics, fluoroquinolones, antiretrovirals, antineoplastic agents and immunosuppressants. The main mechanisms involved are alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Pharmacovigilance signal were found for a majority of drugs or pharmacological classes identified as being at risk of diabetes or hyperglycemia. We identified new pharmacovigilance signals with drugs not known to be at risk according to the literature or official data: phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, sodium oxybate, biphosphonates including alendronic acid, digoxin, sartans, linosipril, diltiazem, verapamil, and darbepoetin alpha. Further studies will be needed to confirm these signals.

Conclusions

The risks of induced hyperglycemia vary from one drug to another, and the underlying mechanisms are multiple and potentially complex. Clinicians need to be vigilant when using at-risk drugs in order to detect and manage these adverse drug reactions. However, it is to emphasize that the benefits of appropriately prescribed treatments most often outweigh their metabolic risks.

For several years, fertility disorders have been on the increase worldwide. These disorders affect both sexes, but are more pronounced in men; and in half of cases the etiology is unknown. The role of drugs in male infertility has been little studied to date. Most of the available data comes from experimental animal studies, with all their limitations. With the exception of a few drugs, such as certain anticancer agents, human data are rare. This article describes the mainly drugs known to have deleterious effects on male fertility, the mechanisms leading to these effects and methods used to assess the risk of drug-induced male infertility. It underlines the need for further work in experimental research, clinical trials and post-marketing surveillance to improve our knowledge of drugs that induce male infertility. Although these adverse effects are not life-threatening, they can have a significant impact on patients’ lives.

Cutaneous adverse drug reactions (ADRs) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Maculopapular exanthema and urticaria are the most common types of cutaneous ADR. Serious cutaneous ADRs, which may cause permanent sequelae or have fatal outcome, may represent 2% of all cutaneous ADR and must be quickly identified to guide their management. These serious reactions include bullous manifestations (epidermal necrolysis i.e. Stevens-Johnson syndrome and toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Some risk factors for developing cutaneous ADRs have been identified, including immunosuppression, autoimmunity or genetic variants. All drugs can cause cutaneous ADRs, the most commonly implicated being antibiotics (especially aminopenicillins and sulfonamides), anticonvulsants, allopurinol, antineoplastic drugs, non-steroidal anti-inflammatory drugs and iodinated contrast media. Pathophysiology is related to immediate or delayed “idiosyncratic” immunologic mechanisms, i.e., usually not related to dose, and pharmacologic/toxic mechanisms, commonly dose-dependent and/or time-dependent. If an immuno-allergic mechanism is suspected, allergological explorations (including epicutaneous patch testing and/or intradermal test) are often possible to clarify drug causality, however these have a variable sensitivity according to the drug and to the ADR type. No in vivo or in vitro test can consistently confirm the drug causality. To determine the origin of a rash, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis (especially infectious etiologies) is required, completed with a literature search. Reporting to pharmacovigilance system is therefore essential both to analyze drug causality at individual level, and to contribute to knowledge of the drug at population level, especially for serious cutaneous ADRs or in cases involving newly marketed drugs.

Introduction

Cancer remains a worldwide threat, having caused almost 10 million deaths in 2020. The American Cancer Society has identified both known and probable carcinogens, including commonly used drugs. The aim of this study is to describe the drugs most frequently reported in the occurrence of cancer.

Methods

Among all individual case safety reports (ICSRs) in the global pharmacovigilance database VigiBase, we searched for the 50 most reported drugs with an adverse drug reaction term belonging to the query “Malignant or unspecified tumors” until June 30, 2023. Then, we extracted the disproportionality measurement data, information component (IC), and reporting odds ratio (ROR) in order to assess a disproportionality signal.

Results

Among all ICSRs in VigiBase, 871,925 contained an ADR belonging to the SMQ “Malignant or unspecified tumors”. Ranitidine was the drug with the most reported ADRs related to cancer (n = 106,484), followed by lenalidomide (n = 13,466), and etanercept (n = 8014). The drugs with the highest IC were ranitidine (IC = 5.2, 95% confidence interval [95% CI] = 5.2–5.2), pioglitazone (1353 ICSRs, IC = 4.2, 95% CI = 4.2–4.2), and regorafenib (1272 ICSRs, IC = 2.8, 95% CI = 2.8–2.8).

Discussion

Our results show that the main pharmacological mechanisms are associated with ranitidine (link with levels of N-nitrosodimethylamine in ranitidine-based drugs), gene-activating drugs (pioglitazone: link with agonist effects on PPAR-γ gene activation), various pharmacological families with immunosuppressive effects (protein kinase inhibitors, immunomodulators, azathioprine, etc.), certain types of protein kinase inhibitors whose oncogenic mechanisms remain unclear (regorafenib, sorafenib, imatinib, ibrutinib, etc.), and hormone antagonists (tamoxifen, letrozole). Special monitoring of patients exposed to these drugs may be required. Further studies are needed to assess the risk with certain drugs in this ranking.

Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.

Studies on drug utilization in western countries disclosed that about nine over ten women use at least one or more drugs during pregnancy. Determining whether a drug is safe or not in pregnant women is a challenge of all times. As a developing organism, the fetus is particularly vulnerable to effects of drugs used by the mother. Historically, research has predominantly focused on birth defects, which represent the most studied adverse pregnancy outcomes. However, drugs can also alter the ongoing process of pregnancy and impede the general growth of the fetus. Finally, adverse drug reactions can theoretically damage all developing systems, organs or tissues, such as the central nervous system or the immune system. This extensive review focuses on different aspects of drug-induced damages affecting the fetus or the newborn/infant, beyond birth defects, which are not addressed here.