Current Drug Safety - Volume 19, Issue 2, 2024

Administering therapeutics through the oral route is a pervasive and widely approved medication administration approach. However, it has been found that many drugs show low systemic absorption when delivered through this route. Such limitations of oral drug delivery can be overcome by polymeric micelles acting as vehicles. As a result, they improve drug absorption by protecting loaded drug substances from the gastrointestinal system's hostile conditions, allowing controlled drug release at a specific site, extending the time spent in the gut through mucoadhesion, and inhibiting the efflux pump from reducing therapeutic agent accumulation. To promote good oral absorption of a weakly water-soluble medicinal drug, the loaded medicine should be protected from the hostile atmosphere of the GI tract. Polymeric micelles can be stacked with a broad assortment of ineffectively dissolvable medications, improving bioavailability. This review discusses the major mechanism, various types, advantages, and limitations for developing the polymeric micelle system and certain micellar drug delivery system applications. The primary goal of this review is to illustrate how polymeric micelles can be used to deliver poorly water-soluble medications.

Background: Pharmacovigilance (PV) deals with the detection, collection, assessment, understanding, and prevention of adverse effects associated with drugs. The objective of PV is to ensure the safety of the medicines and patients by monitoring and reporting all adverse drug reactions (ADRs) associated with prescribed medicine usage. Findings have indicated that about 0.2- 24% of hospitalization cases are due to ADRs, of which 3.7% of patients have lethal ADRs. The reasons include the number of prescribed drugs, an increased number of new medicines in the market, an inadequate PV system for ADR monitoring, and a need for more awareness and knowledge about ADR reporting. Severe ADRs lead to enhanced hospital stays, increased treatment costs, risk of death, and many medical and economic consequences. Therefore, ADR reporting at its first instance is essential to avoid further harmful effects of the prescribed drugs. In India, the rate of ADR reporting is less than 1%, whereas worldwide, it is 5% due to a need for more awareness about PV and ADR monitoring among healthcare providers and patients. The main objective of this review is to highlight the current scenario and possible futuristic ways of ADR reporting methods in rural areas of India. We have searched the literature using PubMed, Google scholar, Indian citation index to retrieve the resources related to ADR monitoring and reporting in India's urban and rural areas. Spontaneous reporting is the most commonly used PV method to report ADRs in India's urban and rural areas. Evidence revealed that no effective ADR reporting mechanisms developed in rural areas causing underreporting of ADR, thus increasing the threat to the rural population. Hence, PV and ADR reporting awareness among healthcare professionals and patients, telecommunication, telemedicine, use of social media and electronic medical records, and artificial intelligence are the potential approaches for prevention, monitoring, and reporting of ADRs in rural areas.

Burns are large open surgical lesions bathed in virulent pus that result in rupturing of the cutaneous membrane, which has serious consequences such as an extensive loss of proteins, and body fluids, increased chances of infections, and sometimes death. These can be classified based on their penetration levels, i.e., first-degree burns penetrating the epidermis, second-degree burns including both epidermis and dermis, third-degree burns to both layers including the hair follicular cells, sweat glands and various core tissues, fourth-degree burns to adipose tissue, fifth stage burns to muscles, and sixth stage burns to bones. Wound healing/wound repair is a very perplexing process in which the tissues of the affected/burnt area repairs themselves to attain their original form and functionality but develop a scar at the wound site. This article mainly focuses on the algorithms to differentiate various degrees of burns, general first aid approaches to burns and scars, the rationale of treatment of burns, basic mechanisms highlighting the healing processes in humans in terms of free from scar formation as well as with scar formation at their elementary levels including cellular as well as biochemical levels, utility, and progression of pre-clinical data to humans and finally approaches for the improvement of scar formation in man.

Epidemiologic studies on the risk of multiple sclerosis (MS) or demyelinating events associated with anti-tumor necrosis factor alpha (TNFα) use among patients with rheumatic diseases or inflammatory bowel diseases have shown conflicting results. Causal directed acyclic graphs (cDAGs) are useful tools for understanding the differing results and identifying the structure of potential contributing biases. Most of the available literature on cDAGs uses language that might be unfamiliar to clinicians. This article demonstrates how cDAGs can be used to determine whether there is a confounder, a mediator or collider-stratification bias and when to adjust for them appropriately. We also use a case study to show how to control for potential biases by drawing a cDAG depicting anti-TNFα use and its potential to contribute to MS onset. Finally, we describe potential biases that might have led to contradictory results in previous studies that examined the effect of anti-TNFα and MS, including confounding, confounding by contraindication, and bias due to measurement error. Clinicians and researchers should be cognizant of confounding, confounding by contraindication, and bias due to measurement error when reviewing future studies on the risk of MS or demyelinating events associated with anti-TNFα use. cDAGs are a useful tool for selecting variables and identifying the structure of different biases that can affect the validity of observational studies.

Phenylalanine, an essential amino acid, is the "building block" of protein. It has a tremendous role in different aspects of metabolic events. The tyrosine pathway is the prime one and is typically used to degrade dietary phenylalanine. Phenylalanine exceeds its limit in bodily fluids and the brain when the enzyme, phenylalanine decarboxylase, phenylalanine transaminase, phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4) is deficient causes phenylketonuria, schizophrenia, attentiondeficit/ hyperactivity disorder and another neuronal effect. Tyrosine, an amino acid necessary for synthesizing the pigments in melanin, is produced by its primary metabolic pathway. Deficiency/abnormality in metabolic enzymes responsible for the catabolism pathway of Phenylalanine causes an accumulation of the active intermediate metabolite, resulting in several abnormalities, such as developmental delay, tyrosinemias, alkaptonuria, albinism, hypotension and several other undesirable conditions. Dietary restriction of the amino acid(s) can be a therapeutic approach to avoid such undesirable conditions when the level of metabolic enzyme is unpredictable. After properly identifying the enzymatic level, specific pathophysiological conditions can be managed more efficiently.

Introduction: Paracetamol (Acetaminophen) is a very common OTC drug that is found in more than 200 OTC products sold as pain, cough and cold remedies. Paracetamol is commonly used as an antipyretic to reduce fever and as an alternative to Non-steroidal anti-inflammatory drugs (NSAIDs) that are contraindicated in certain patients to relieve mild-moderate pain.Objective: This review article focuses on SJS, TEN, SJS/TEN overlap, AGEP, and DRESS syndromes associated with the use of paracetamol or paracetamol-containing products.Methods: To find published articles relevant to paracetamol-associated SJS, TEN, AGEP, and DRESS, we searched the online databases Medline/Pubmed/PMC, Google Scholar, Science Direct, Ebsco, Scopus, Web of Science, Embase, and reference lists using keywords like Stevens-Johnson Syndrome, Acetaminophen, Paracetamol, Toxic epidermal necrolysis, Acute generalized exanthematous pustulosis, Drug reaction with eosinophilia and systemic symptoms.Results: The paracetamol-associated SJS, TEN, SJS/TEN overlap, AGEP, and DRESS syndromes have been identified by a number of publications.Conclusion: When evaluating drug-induced hypersensitivity skin reactions, healthcare professionals, including prescribers, pharmacists, and others, should be aware of this rare risk. Patients who exhibit signs and symptoms of paracetamol-associated hypersensitivity should be referred to physicians by pharmacists for further treatment. At the first sign of a skin rash or other hypersensitivity reaction while taking paracetamol, patients should be told to stop taking it and see a doctor right away.

Toxicity associated with low doses of methotrexate (MTX) is low, but it may be fatal. Bone marrow suppression and mucositis are among the common side effects of low dose MTX toxicity. Different risk factors have been reported for toxicities associated with low doses of MTX, including accidental use of higher doses, renal dysfunction, hypoalbuminemia, and polypharmacy. In this paper, we present a female patient who had mistakenly used 7.5 mg of MTX daily instead of the same dose of MTX on Thursday and Friday. She was presented with mucositis and diarrhea to the emergency department. Moreover, we searched the databases Scopus and PubMed for available studies and case reports on toxicities associated with MTX dosing errors. The most frequently observed toxicities included gastrointestinal lesions, nausea, vomiting, skin lesions, and bone marrow suppression. Leucovorin, hydration, and urine alkalinization were among the most frequently used treatments. Finally, we summarize the data on the toxicities of low doses of MTX in different diseases.

Introduction: Glycaemic variability is possibly linked to the development of diabetic retinopathy, and newer second-line glucose-lowering treatments in type 2 diabetes might reduce glycaemic variability.Aim: This study aimed to investigate whether newer second-line glucose-lowering treatments are associated with an alternative risk of developing diabetic retinopathy in people with type 2 diabetes.Methods: A nationwide cohort of people with type 2 diabetes on second-line glucose-lowering treatment regimens in 2008-2018 was extracted from the Danish National Patient Registry. Adjusted time to diabetic retinopathy was estimated with a Cox Proportional Hazards model. The model was adjusted for age, sex, diabetes duration, alcohol abuse, treatment start year, education, income, history of late-diabetic complications, history of non-fatal major adverse cardiovascular events, history of chronic kidney disease, and history of hypoglycaemic episodes.Results: Treatment regimens of metformin + basal insulin (HR: 3.15, 95% CI: 2.42-4.10) and metformin + glucagon-like peptide-1 receptor agonist (GLP-1-RA, HR: 1.46, 95% CI: 1.09-1.96) were associated with an increased risk of diabetic retinopathy compared with metformin + dipeptidyl peptidase-4 inhibitors (DPP-4i). Treatment with metformin + sodium-glucose cotransporter-2 inhibitor (SGLT2i, HR: 0.77, 95% CI: 0.28-2.11) was associated with the numerically lowest risk of diabetic retinopathy compared with all regimens investigated.Conclusion: Findings from this study indicate that basal insulin and GLP-1-RA are suboptimal second- line choices for people with type 2 diabetes at risk of developing diabetic retinopathy. However, many other considerations concerning the choice of second-line glucose-lowering treatment for type 2 diabetes patients should be taken into account.

Background: Proton pump inhibitors (PPIs) are one of the most used classes of drugs. For most indications, PPIs are only recommended up to 8 weeks duration. However, PPI use continues to expand. Regular and prolonged use of PPIs should be avoided because of the risk of adverse events.Objectives: The main objective of this study was to (1) investigate the extent of PPI usage in people aged 65 or older in the province of British Columbia (BC), Canada, (2) provide an overview of the harms associated with the long-term use of PPIs.Methods: We examined utilization trends of the PPIs in BC since the year 2009 using PharmaNet, BC's medication dispensing database where the information is accessible to community pharmacists. We performed a comprehensive literature search for relevant reviews reporting harms associated with long-term use of PPIs. A search was conducted from January 2014 to June 2022.Results: Between 2000 and 2018 BC's population grew by 20%, but the use of PPIs escalated to 257%. Of these older British Columbians, 62% had a cumulative exposure exceeding 2 years and 42% exceeded 5 years. This is alarming because the recommended treatment duration is 4-12 weeks for common indications including reflux esophagitis, and duodenal and gastric ulcers. Only 13.5% were dispensed PPIs for 90 days or less. Patients on long-term PPI therapy should be reassessed. Adverse events of PPI use are common among older adults. We identified over 217 systematic reviews published during the last 8 years of specific harms associated with long-term daily usage of PPIs. These harms include increased risks of death, cardiovascular disease, acute renal injury, chronic kidney disease, dementia, fractures, hypomagnesemia, iron deficiency, vitamin B12 deficiency, enteric infection (including C. difficile), pneumonia, and neoplasia (gastric cancer, carcinoids, and colon cancer), and drug interactions.Conclusion: This study revealed a high prevalence of PPI use among elderly populations in BC, Canada. The overutilization of PPIs is often a result of failure to re-evaluate the need for continuation of therapy. Published studies identified signals of serious harm from long-term PPI exposure. Healthcare providers with patients can reverse the relentless expansion of long-term PPI exposure by discussing the expected benefits and potential harms.

Background: Vaccination against COVID-19 virus is the most valuable tool available for protection during the pandemic of coronavirus. The clinical manifestation post-vaccination is a barrier to vaccination for many people in Iraq and worldwide.Objectives: The objective of this study is identifying various clinical manifestations occurring after receiving vaccines among individuals in Basrah Governorate. Moreover, we examine its association with respondents' demographics and the type of vaccine they received.Methods: A cross-section study was conducted in Basrah, southern Iraq. Research data were collected through an online questionnaire. The data were analyzed using both descriptive and analytic statistical tools using the SPSS program.Results: Most of the participants (86.68%) received the vaccine. The side effects were reported in 71.61% of vaccinated individuals. Fever and muscle pain were the two most experienced clinical manifestations, while lymph node enlargement and disturbances in taste and/or smell sensations were reported infrequently. Adverse effects were mostly reported with the Pfizer BioNTech vaccine receiver. Females and those in the younger age group also reported a significantly higher incidence of side effects.Conclusion: Most adverse effects related to the COVID-19 vaccine were minor and could be tolerated without the need for hospital admission.

Background: Over the past few years, major inspection findings have been identified in the "management of adverse reactions" that may be due to increasing workload in pharmaceutical organizations impacting the correctness of information in individual case safety reports (ICSRs). Although retrospective quality check (Retro-QC) and late submission analyses are important steps in ensuring ICSR quality, their manual application poses several challenges that can be overcome through automation.Objectives: To improve the efficiency of the Retro-QC analysis and late submission analysis using a computer-operated tool called Compliance and Metrics Management (CMM) tool, and to measure the tool's effectiveness in terms of productivity, time, and cost savings by comparing against the manual process.Methods: Time savings were calculated by measuring the difference in time taken during the manual process versus the automated process. Cost savings were measured in terms of hourly remuneration for the time saved. Productivity was calculated as the difference between the number of cases handled in the manual versus automated process. Thus, the overall efficiency was measured in terms of time and cost savings along with increased productivity.Results: Automation resulted in time savings of 49% and cost savings of 43% for Retro-QC analysis, and the productivity level increased by 67%. For late submission analysis, the CMM tool resulted in time savings of 88% and cost savings of 87%.Conclusion: CMM tool enhanced the efficiency of both Retro-QC and late submission analyses by increasing productivity along with time and cost savings. It also reduced the number of errors, thereby enhancing the accuracy of the process and overall compliance.

Background: Prior research has suggested buprenorphine-containing medications may be associated with an increased risk of dental disorders. However, published data describing adverse dental reactions in buprenorphine users by active ingredient composition and route of administration are limited.Objective: The purpose of this study was to evaluate the influence of formulation on spontaneous reporting of dental disorders among patients treated with buprenorphine.Methods: Adverse event reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) between 2015 and 2022 were analyzed. Reporting odds ratios (ROR) and 95% confidence intervals (CI) were calculated to measure disproportionality of dental disorder reporting as classified by 39 Medical Dictionary for Regulatory Activities preferred terms.Results: Compared to pooled reports for all other drugs across FAERS, both buprenorphine monotherapy (ROR 3.09; 95% CI 2.61-3.66) and combination buprenorphine/naloxone (ROR 14.61; 95% CI 13.34-16.01) were associated with positive disproportionality signals. Signals of disproportionate dental disorder reporting were also detected for buprenorphine medicines administered by sublingual (ROR 20.03; 95% CI 18.04-22.24), buccal (ROR 4.46; 95% CI 3.00-6.61) and oral (ROR 7.17; 95% CI 5.03-10.22) routes, but not for other modalities. In considering active ingredient and route together, sublingual buprenorphine monotherapies (ROR 23.55; 95% CI 17.84-31.11) and sublingual buprenorphine/naloxone (ROR 19.47; 95% CI 17.39-21.80) were each associated with disproportionate reporting of dental disorders.Conclusion: Subject to the limitations of spontaneous adverse event data, this study identified significantly disproportionate reporting of dental disorders to FAERS among patients treated with buprenorphine- containing medications, including formulations administered by sublingual, buccal and oral routes. These findings are consistent with prior data and suggest that regular oral care and proper dental hygiene be emphasized for patients undergoing therapy with orally dissolving buprenorphine.

Background: Low confidence in the safety of COVID-19 vaccines was found to be a key promoter of vaccine reluctance especially among youth. Furthermore, young adults are an important demographic for building herd immunity through vaccination. As a result, their reactions to getting COVID-19 vaccines are crucial in our fight against SARS-CoV-2.Objective: The overall goal of this study was to look into the shortterm side effects experienced by Moroccan medical and pharmacy students after receiving COVID-19 vaccines.Methods: A cross-sectional survey-based study to assess the COVID-19 vaccines' short-term AEFIs among Moroccan medical and pharmacy students. The validated questionnaire was delivered in a digital form to explore the side effects (SE) they encountered after the first or the second dose of one of three vaccines namely: AstraZeneca Vaxzevria, PfizerBioNTeck, and SinoPharm vaccines.Results: There were 510 students in total who took part. After the first and second doses, approximately 72 percent and 78 percent of subjects, respectively, reported no SE. The remainder had localized injection site side effects (26%). Fatigue (21%), fever (19%), headache (17%), and myalgia (16%) were the most common systemic adverse effects after the first dose. There were no serious SEs reported.Conclusion: The majority of the reported AEFIs in our data were mild to moderate in intensity and lasted only one or two days. COVID-19 vaccinations are highly likely safe for young adults, according to the findings of this study.

Introduction: Intravenous sedation and analgesia are widely used in minor surgeries. Remifentanil and remimazolam are advantageous in this setting because of their rapid onset of action, and short duration of action leading to a rapid recovery. However, the two drugs combined need to be titrated to avoid airway-related adverse events.Case Presentation: This article reports a case of severe respiratory depression and severe laryngeal spasm induced by remifentanil and remimazolam when they were used for analgesia and sedation in a patient undergoing oral biopsy.Conclusion: We aim to improve awareness about the safety of these drugs among anesthesiologists and increase their ability to manage the risk associated with their use.

Introduction: Adverse drug reactions (ADR) are defined as any harmful or unpleasant events or injuries resulting from the use of any particular drug. Among those antibiotics that cause adverse reactions, amoxicillin is one of them. Catatonia and vasculitic rash are its rare adverse effects.Case Presentation: A 23-year-old postpartum female, with a history of taking empirical Amoxiclav (amoxicillin-clavulanic acid 625 mg) injection and oral tablets for episiotomy wound, presented with altered sensorium and fever followed by maculopapular rash. On examination, she had generalized rigidity with waxy flexibility that improved by lorazepam challenge and was diagnosed as catatonia. On evaluation, amoxicillin was found to be precipitating catatonia in this patient.Conclusion: Since the diagnosis of catatonia is often missed, any cases with clinical presentation of fever, rash, altered sensorium, and generalized rigidity should also be suspected for druginduced ADR and the precipitating factor should be searched for.

Background: Toxic Epidermal Necrolysis (TEN) is a rare, acute, and life-threatening mucocutaneous disease that occurs after the administration of certain drugs, resulting in extensive keratinocyte cell death, skin involvement at the dermal-epidermal junction, and extensive bullous skin eruptions and sloughing. Many published case reports have observed the presence of fever with a viral infection, drug, and/or genetic association as a possible trigger for TEN but associated with other comorbidities. Physicians still struggle to predict which individuals could be predisposed to TEN. The case report that we present had a history of multiple drug intake and fever due to dengue virus infection but was not associated with any other comorbidity.Case Presentation: We present an unusual case of a 32-year-old woman of Western Indian origin who had developed dengue infection and suffered toxic epidermal necrolysis following a five-day course of a third-generation cephalosporin antibiotic, cefixime and a three-day course of 2 analgesic drugs, paracetamol (acetaminophen), and nimesulide, with the adverse event occurring on the fifth day of the dengue infection. The offending drugs were stopped, and patient survived with supportive management and hydration.Conclusion: The presence of comorbidities may not always be the triggering factor for TEN, though it can affect patient outcomes. Rational drug use is always recommended for patient care. Further research is required to understand the pathomechanism behind the viral-drug-gene interaction.

Background: Phenylephrine is a sympathomimetic, which means it acts analogous to adrenaline. Phenylephrine can be taken orally to treat nasal congestion symptoms. It is also frequently mixed with other medicines in products meant to relieve cough and cold symptoms. Given the widespread usage of phenylephrine, related drug eruptions appear to be uncommon.Case Presentation: Here we discuss a case of a 19-year-old female patient who reported to our hospital with blebs on the skin throughout her legs and torso. The drug eruption or adverse drug response was linked with itching, had a slow beginning, and progressed. Her medical history indicated that she had been taking phenylephrine 10 mg orally twice a day. On the sixth day, she experienced an adverse medication response caused by the medicine phenylephrine. Phenylephrine was stopped immediately and the other medications, such as levocetirizine, montelukast, and nasal spray, were continued. The patient was told not to use phenylephrine, either alone or in combination with FDCs. There are no other complaints. As a result, the patient was diagnosed with phenylephrine- induced eruption.Conclusion: We present this case to highlight the importance of inspiring a pharmacovigilance mindset among all clinicians providing care as a routine alert drug, phenylephrine-induced drug eruption.

Introduction: Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) are severe adverse drug reactions characterized by widespread blistering and mucositis. Wilson's disease is a rare, autosomal recessive disorder that results in excessive copper accumulation in the body, where penicillamine is an effective treatment option for copper chelation. Penicillamineinduced SJS-TEN is a rare but potentially fatal adverse effect. There is increased susceptibility to SJS/TEN in HIV infection due to immunosuppression and chronic liver disease due to impaired hepatic function.Objective: To diagnose and manage the occurrence of the rare severe adverse cutaneous drug reactions in the backdrop of immunosuppression and chronic liver disease.Case Report: We are reporting penicillamine-induced SJS-TEN overlap in a 30-year-old male with Wilson's disease, HIV and Hepatitis B who was treated with intravenous immunoglobulins. The patient later developed neurotrophic ulcer in the right cornea as a delayed sequela.Conclusion: Our case report emphasizes that there is an increased predisposition to SJS/TEN in immunocompromised and chronic liver disease patients. Physicians should be well aware of the potential danger of SJS/TEN in this subset of patients, even while prescribing a relatively safer drug.