Drug-induced radiation recall reactions and non-anticancer drugs: A descriptive analysis from VigiBase®

Radiation recall reactions are inflammatory reactions confined to previously irradiated tissues, often of drug-induced etiology, particularly with anticancer therapies. Other drugs, in particular COVID-19 vaccines, may also be involved. To describe radiation recall reactions under non-anticancer drugs more precisely, we extracted the cases of radiation recall reactions associated with non-anticancer drugs from WHO pharmacovigilance database VigiBase®. We performed two analyses from this extraction: a global analysis and an analysis focusing on vaccination-related issues. We extracted 120 cases corresponding to 269 drugs, of which 130 were non-anticancer (22 vaccines). Among the non-anticancer drugs, tozinameran was the most reported treatment (4.46% of cases), followed by levofloxacin (2.97%) and folinic acid (2.60%), dexamethasone (2.23), and ChAdOx1 nCoV-19 vaccine and prednisone (1.86% each). Among vaccines, tozinameran (54.55% of cases) was the most reported, followed by ChAdOx1 nCoV-19 (22.73%), HPV and inactivated influenza vaccine (9.09% each), and elasomeran (4.55%). Our study first describes the occurrence of radiation recall reactions during non-anticancer treatment. It also highlights a potential safety signal with COVID-19 vaccines.     

FabAct®: a decision-making tool for the anticipation of the preparation of anticancer drugs

Rationale Due to the increase of new cancer cases, our chemotherapy compounding unit must face with ever‐growing production needs. To support this increasing workload, we decided to anticipate the preparation of several anti‐cancer drugs. Aims and objectives To help us in the decision making, we needed a modern tool able to combine several criteria for selecting appropriate medications for an anticipated preparation. The aim of this study was to assess the decision‐making software, FabAct^® (Version 1.0). Methods FabAct^® ranked all of the anti‐cancer drugs used in our chemotherapy compounding unit according to price, chemical stability, compounding difficulties, dosage and production per year. Then, we started to anticipate currently the preparation of four medications and conducted a follow‐up of destroyed preparations between January and May 2007. We tried to identify the destruction causes and calculated the time saved for the patients and for the pharmacy technicians. Results According to the decision‐making software, the first four drugs for an anticipated preparation were: fluorouracil, cisplatin, carboplatin and paclitaxel. A total of 3913 (50.2%) anticipated preparations were performed and among those, 470 (12%) were destroyed. The main cause of destruction was due to the preparation expiration. Finally, the mean waiting time per patient was reduced from 118 minutes to 68 minutes after the application of the anticipated model. Conclusion According to this 5‐month follow‐up, FabAct^® helped us to select appropriate anti‐cancer drugs to anticipate the compounding. Most of the anticipated preparations were administrated to patients and the patient waiting time was significantly reduced.     

Are migraineurs at increased risk of adverse drug responses? A meta-analytic comparison of topiramate-related adverse drug reactions in epilepsy and migraine

To compare adverse drug reactions (ADRs) to topiramate in patients with migraine and patients with epilepsy, we systematically reviewed all published randomized controlled trials (RCTs) that compare topiramate monotherapy in epilepsy and migraine. We included four epilepsy RCTs (N = 1,179 patients; vs. active comparators) and six migraine RCTs (N = 1,723 patients; vs. placebo). Behavioral ADRs and headache were found only in the case of epilepsy, whereas cognitive complaints and alteration of taste were found only in the case of migraine. The risk ratios (RRs) for paresthesia in migraine vs. epilepsy trials were 2.5 (99% confidence interval (CI): 1.66-3.77) for 50 mg, 2.7 (99% CI: 1.80-3.97) for 100 mg, and 3.0 (99% CI: 1.95-4.56) for 200 mg. For ADR-related dropouts, the RR was 2.5 (95% CI: 2.03-2.98) for 50 mg but no different for the other doses. We conclude that when treated with the same doses of topiramate, migraineurs show different ADRs than patients with epilepsy and are more likely to drop out because of ADRs.     

Are the Naranjo criteria reliable and valid for determination of adverse drug reactions in the intensive care unit?

BACKGROUND: The Naranjo criteria are frequently used for determination of causality for suspected adverse drug reactions (ADRs); however, the psychometric properties have not been studied in the critically ill. OBJECTIVE: To evaluate the reliability and validity of the Naranjo criteria for ADR determination in the intensive care unit (ICU). METHODS: All patients admitted to a surgical ICU during a 3-month period were enrolled. Four raters independently reviewed 142 suspected ADRs using the Naranjo criteria (review 1). Raters evaluated the 142 suspected ADRs 3-4 weeks later, again using the Naranjo criteria (review 2). Inter-rater reliability was tested using the kappa statistic. The weighted kappa statistic was calculated between reviews 1 and 2 for the intra-rater reliability of each rater. Cronbach alpha was computed to assess the inter-item consistency correlation. The Naranjo criteria were compared with expert opinion for criterion validity for each rater and reported as a Spearman rank (r(s)) coefficient. RESULTS: The kappa statistic ranged from 0.14 to 0.33, reflecting poor inter-rater agreement. The weighted kappa within raters was 0.5402-0.9371. The Cronbach alpha ranged from 0.443 to 0.660, which is considered moderate to good. The r(s) coefficient range was 0.385-0.545; all r(s) coefficients were statistically significant (p < 0.05). CONCLUSIONS: Inter-rater reliability is marginal; however, within-rater evaluation appears to be consistent. The inter-item correlation is expected to be higher since all questions pertain to ADRs. Overall, the Naranjo criteria need modification for use in the ICU to improve reliability, validity, and clinical usefulness.     

Life-threatening adverse drug reactions at admission to medical intensive care: a prospective study in a teaching hospital

Objective To assess the characteristics of life-threatening adverse drug reactions in patients admitted to medical intensive care unit and to define those that could facilitate early identification. Design A prospective 6-month observational study. Patients Of the 436 admissions to the teaching hospital medical intensive care unit, all patients aged over 15 years and who had received documented drug treatment were included (n = 405). Measurements Characteristics of patients [age, gender, underlying diseases, organ failure(s), drugs taken, Severity Acute Physiologic Score II, length of stay, outcome at discharge] were prospectively collected using a standardised questionnaire. A panel of experts assessed putative serious adverse drug reaction(s) for each drug taken and each organ failure at admission by using a standardised causality assessment method. Characteristics of patients with and without serious adverse drug reactions at admission were compared using univariate and then stepwise descending multivariate logistic regression. Results Of the 405 patients included, 111 (27.4%) presented an adverse drug reaction leading to organ failure. In 48% of cases adverse drug reactions were preventable, 23% were undiagnosed and 19% contributed to death. Age over 75 years [odds ratio (OR) 2.25; 95% confidence interval (CI) 1.15–4.38; p = 0.02], having more than three drugs (OR 6.90; 95% CI 1.44–33.00; p = 0.02) and a diagnosis of haematological malignancy (OR 6.19; 95% CI 2.07–18.53; p = 0.001) were independently associated with serious adverse drug reactions. Conclusions Preventable life-threatening adverse drug reactions were frequently involved in organ failure at admission to medical intensive care; many of them had not been identified. Financial disclosures: None Conflict of interest: None     

The ten most common adverse drug reactions (ADRs) in oncology patients: do they matter to you?

Aims To assess incidence, predictability, preventability and severity of adverse drug reactions (ADRs) in hospitalised oncology patients.Patients and methods Patients hospitalised at Peter MacCallum Cancer Centre from 28 February to 2 June 2000 were selected for interviews about symptoms related to their drug therapy. Medical records were also reviewed. Causality, predictability, preventability and severity were assessed for each ADR.Results One hundred and sixty-seven patients associated with 171 admissions were interviewed. Four hundred and fifty-four ADRs were identified in 127 (74.3%) separate admissions (mean ADRs per admission 2.7; range 0–18). Eighty-eight percent of ADRs were predictable. Of these, 1.6% was classified as definitely preventable and 46.1% probably preventable. The ten most common ADRs were constipation, nausea ± vomiting, fatigue, alopecia, drowsiness, myelosuppression, skin reactions, anorexia, mucositis and diarrhoea. These ADRs have high-documented incidence rates and were also the ten most predictable ADRs in this study. Common reasons for ADRs to be assessed as definitely or probably preventable were omission or inadequate/inappropriate use of preventative measures. The results also showed a discrepancy between clinical severity and patients perception of the impact of ADRs on well being.Conclusions ADRs are common in hospitalised oncology patients and are predictable and at least probably preventable in many instances. Improved use of preventative measures has the potential to contribute to reducing the incidence and severity of ADRs. Recognition and understanding of the discrepancy that exists between clinical severity and patient-perceived severity of ADRs will enable specific areas to be identified and targeted for vigourous intervention.     

Is it food allergy? Differentiating the causes of adverse reactions to food

Foods can produce adverse symptoms in various ways, and the patient's history can help determine whether allergy or some other mechanism is responsible. The history has limitations, however, as it is primarily subjective. Therefore, diagnostic confirmation is very important. Strict avoidance of the allergenic food is the primary course of treatment. Education is imperative to ensure that patients understand food labels and recognize the different names used to designate a specific food. Prompt treatment with epinephrine when an acute reaction occurs can make a life-or-death difference.     

Parents' experiences of handling oral anticancer drugs at home: ‘It all falls on me …’

Aim

The aim of this study was to describe the experiences of parents handling oral anticancer drugs in a home setting.

Methods

Parents of children with cancer were recruited from a paediatric oncology ward in Sweden to participate in an interview. The interviews were transcribed verbatim and subjected to qualitative content analysis.

Results

We found the following categories and subcategories: parents’ views on the provided information—lack of, too little or contradictory information, and parents’ preferences for information delivery; safety over time; correct drug dose; and drug administration. As time passed, most parents adapted to their child's illness, felt safer and found it easier to take in and process any given information. Parents preferred information in different formats (written, movie clips and orally) and in their mother tongue. Many parents were aware of the importance of giving an accurate dose to their child and described the process of drug administration as overwhelming.

Conclusion

Parents need to be provided with accurate, timely, nonconflicting and repeated information—in different forms and in their mother tongue—on how to handle oral anticancer drugs at home.     

Are lipid‐lowering drugs associated with a risk of cataract? A pharmacovigilance study

Some reports have raised concerns regarding a potential risk of cataracts associated with statins. However, clinical and observational studies evaluating the risk led to conflicting results. We assessed whether lipid‐lowering drugs (LLD) use is associated with an increased risk of cataract using the WHO's Individual Case Safety Reports database, VigiBase^®. We performed a disproportionality analysis with all reports between 1/1/1988 and 12/31/2018 to measure the reporting risk of ‘cataract’ in patients ≥45 years. Primary analysis compared LLD users to non‐users. To mitigate some potential confounding bias, we performed several sensitivity analyses excluding reports (i) with an association of at least two LLD, (ii) with antidiabetic and glucocorticoids and (iii) with lovastatin. We also analyzed the data according to the different classes of age limiting the period of study to years 2002–2012. We identified 14 664 reports of cataract (3 049 in LLD users, 66% women, 66 ± 20 years). Statins (84%, atorvastatin, simvastatin, rosuvastatin and lovastatin) were mostly reported, followed by fibrates (5.7%), nicotinic acid (3%), bile acid sequestrants (2%), herbal cholesterol and triglyceride reducers (2%) and others (ezetimibe, PCSK9 inhibitors, 15%). LLD users were associated with a greater risk of reports than non‐users (ROR 2.47, 95% CI 2.37–2.57). This association was also found for statins in general, fibrates, bile sequestrants, nicotinic acid, herbal drugs and others. Similar trends were observed in sensitivity analyses (except for fibrates and nicotinic acid after exclusion of reports with at least two LLD or in older patients ≥75 years). Using a large real‐life database (>18.5 million reports), we found a signal of cataract for LLD as a whole and statins, bile sequestrants and herbal drugs in particular. The signal disappeared for fibrates and nicotinic acid in older patients. No definite conclusions can be made for ezetimibe or PCSK9 inhibitors (evolocumab and alirocumab). This suggests that a decrease in cholesterol could be important in the pathophysiology of cataract in patients exposed to the main LLD.     

Efficacy and safety of the remOVE System for OTSC® and FTRD® clip removal: data from a PMCF analysis

Introduction: The remOVE System (Ovesco Endoscopy AG, Tuebingen, Germany) is a medical device for the endoscopic removal of OTSC or FTRD clips (Ovesco Endoscopy AG, Tuebingen, Germany). The aim of this paper is to assess the efficacy and safety of this system.

Material and methods: A total of 74 patients underwent clip extraction. The standard removal procedure comprises fragmenting the clip by applying an electrical direct current pulse at two opposing sides of the clip.

Results: Clip fragmentation was successful in 72 of 74 patients (97.3%). In two cases (2.7%) clip fragmentation was not possible. In nine cases (12.2%) a clip fragment could not be removed and was left in place. Complications occurred in three cases (4.1%): two minor bleedings near the clip removal site (2.7%), and one superficial mucosal tear resulting from clip fragment extraction (1.4%).

Discussion: Based on this study, the use of the remOVE System for OTSC or FTRD clip removal can be considered safe and effective.     

Harm in homeopathy: aggravations, adverse drug events or medication errors?

BACKGROUND: The assessment of harm arising from the use of homeopathic medicine is much discussed, but there is little published data on the subject. AIM: To study prospectively adverse drug events related to homeopathic medicines. SETTING: The data were gathered between 1 June 2003 and 30 June 2004 during follow-up visits consecutively carried out at the Homeopathic Clinic, Campo di Marte Hospital, Azienda USL 2, Lucca (Italy). They refer to effects following the administration of a homeopathic medicine, prescribed according to the classical homeopathic method. METHODS: Reports collected by a homeopathic doctor (not the prescribing doctor) on the nature and intensity of the effect, dose and frequency of administration, time relationship between the drug use and the adverse events, challenge, unchallenge possible concomitant factors, causality (improbable, unlikely, possible, probable, certain). RESULTS: Out of 335 homeopathic consecutive follow-up visits between 1 June 2003 and 30 June 2004, nine adverse reactions were reported (2.68%) including one case of allergy to lactose, excipient of the granules. CONCLUSIONS: Adverse events to homeopathic drugs exist and are distinguishable from homeopathic aggravations, but are rare and not severe.     

Challenges to the development of bryostatin-type anticancer drugs based on the activation mechanism of protein kinase Cδ

Protein kinase C (PKC) isozymes are widely recognized as targets for anticancer therapy, and recent investigations demonstrated that PKC activators are potential therapeutic candidates for Alzheimer's disease and acquired immune deficiency syndrome. However, concerns exist about their therapeutic uses because most PKC activators are potent tumor promoters. Bryostatin 1 (bryo-1) is a unique PKC activator with little tumor-promoting activities. Bryo-1 is currently undergoing clinical trials for the treatment of cancer. However, its limited availability from natural sources and difficulty in the synthesis hamper further studies on its mode of action and structural optimization. Although excellent practical methods for synthesizing several bryo-1-related compounds have been developed, the identification of synthetically more accessible compounds with bryo-1-like activity also provides a promising way to circumvent the problem of supply. The authors focused on the bryo-1's unique mechanism of activating PKCδ that plays a tumor suppressor role, and found that a simple and less lipophilic analogue (aplog-1) of the tumor-promoting aplysiatoxin showed PKCδ-activating behavior similar to bryo-1. Aplog-1 was easily synthesized in only 22 steps using standard reactions. Moreover, its tumor-promoting activity in vitro was very weak, and its cell growth-inhibitory activities were comparable to those of bryo-1. These data suggest that aplog-1 could become another therapeutic lead for cancer.