Efficacy of repetitive transcranial magnetic stimulation (rTMS) adjunctive therapy for major depressive disorder (MDD) after two antidepressant treatment failures: meta-analysis of randomized sham-controlled trials.

BACKGROUND: Several meta-analyses demonstrated the efficacy of unilateral High-Frequency Left-sided (HFL) repetitive Transcranial Magnetic Stimulation (rTMS) for individuals with Major Depressive Disorder (MDD); however, results are contradictory due to heterogeneity of the included studies. METHODS: A systematic literature review (SLR) of English language articles published since 2000 was performed in March 2022 on PubMed and Scopus databases. Empirical evidence on the relative efficacy of rTMS treatment compared with standard pharmacotherapy in Treatment-Resistant Depression (TRD) were extracted. Random effects models were used to assess the effects of rTMS on response and remission rates. RESULTS: 19 randomized double-blinded sham-controlled studies were included for quantitative analysis for response (n = 854 patients) and 9 studies for remission (n = 551 patients). The risk ratio (RR) for response and remission are 2.25 and 2.78, respectively for patients after two treatment failures using rTMS as add-on treatment compared to standard pharmacotherapy. Cochrane's Q test showed no significant heterogeneity. No publication bias was detected. CONCLUSIONS: rTMS is significantly more effective than sham rTMS in TRD in response and remission outcomes and may be beneficial as an adjunctive treatment in patients with MDD after two treatment failures. This finding is consistent with previous meta-analyses; however, the effect size was smaller than in the formerly published literature.

Quality of dorzolamide hydrochloride and timolol maleate containing eye drops distributed online.

Patient safety risks associated with the online purchase of medications, especially in case of ophthalmic preparations, are significant. Our study aimed to carry out quality assessment of dorzolamide hydrochloride (DZA) and timolol maleate (TIM) eye drops preserved with benzalkonium chloride (BAC) via online test purchases. Three samples were purchased online, while control preparations were acquired through authorized national drug supply chain. Our method was based on the International Pharmaceutical Federation (FIP) Inspection Checklist and integrated the evaluation of packaging and labelling. Sterility was established according to the European Pharmacopoeia (Ph. Eur.), while qualitative and quantitative quality was assessed with high-performance liquid chromatographic (HPLC) analysis. Several signs of falsification were recognized upon visual inspection of the online samples. All the products were clear, colourless, slightly viscous solutions. They were free from visible contaminants. The samples were sterile as no evidence of microbial growth was found. A quick and inexpensive HPLC analysis, optimized by the authors showed that active ingredients and the preservative deviated significantly (p < 0,05) with more than 10% from the values stated on the labels for at least one component (DZA: 99.3-113.1%, TIM: 112.8-139.2%, BAC: 82.4-97.7%). Development of comprehensive and reliable quality assessment methods are vital to increase public safety of pharmaceutical products sold online. A complex approach, integrating visual inspection, labelling assessment, microbiological analysis coupled with qualitative and quantitative methods provide a most reliable method. Due to its limited feasibility and cost-effectiveness, raising public awareness and limiting illegal online sellers should be the primary approaches to protect patients from substandard and falsified medicinal products sold via the internet. Particularly important for health professionals to understand this market and its public health concern, and to raise patient awareness of the risks associated with uncontrolled online purchase of medication.

Probing the Interactions of 31 Mycotoxins with Xanthine Oxidase: Alternariol, Alternariol-3-Sulfate, and α-Zearalenol Are Allosteric Inhibitors of the Enzyme.

Mycotoxins are frequent toxic contaminants in foods and beverages, causing a significant health threat. Interactions of mycotoxins with biotransformation enzymes (e.g., cytochrome P450 enzymes, sulfotransferases, and uridine 5'-diphospho-glucuronosyltransferases) may be important due to their possible detoxification or toxic activation during enzymatic processes. Furthermore, mycotoxin-induced enzyme inhibition may affect the biotransformation of other molecules. A recent study described the strong inhibitory effects of alternariol and alternariol-9-methylether on the xanthine oxidase (XO) enzyme. Therefore, we aimed to test the impacts of 31 mycotoxins (including the masked/modified derivatives of alternariol and alternariol-9-methylether) on XO-catalyzed uric acid formation. Besides the in vitro enzyme incubation assays, mycotoxin depletion experiments and modeling studies were performed. Among the mycotoxins tested, alternariol, alternariol-3-sulfate, and α-zearalenol showed moderate inhibitory actions on the enzyme, representing more than tenfold weaker impacts compared with the positive control inhibitor allopurinol. In mycotoxin depletion assays, XO did not affect the concentrations of alternariol, alternariol-3-sulfate, and α-zearalenol in the incubates; thus, these compounds are inhibitors but not substrates of the enzyme. Experimental data and modeling studies suggest the reversible, allosteric inhibition of XO by these three mycotoxins. Our results help the better understanding of the toxicokinetic interactions of mycotoxins.

Safety and risks of CBD oils purchased online: unveiling uncertain quality and vague health claims.

Introduction: The unmet need for highly effective, naturally derived products with minimal side effects results in the over-popularity of ever-newer medicinal plants. In the middle of 2010, products containing cannabidiol (CBD), one of the special metabolites of Cannabis sativa, started to gain popularity. For consumers and healthcare providers alike, the legal context surrounding the marketing of CBD products is not entirely clear, and the safety of using some products is in doubt. Companies in the online medicinal product market profit from the confusion around CBD oils. Methods: In our study, we employed a complex method known as risk-based safety mapping of the online pharmaceutical market, which included health claim content analysis of online stores, test purchases, and labeling and quantitative analysis of the CBD content. Results: There were discovered 16 online retailers selling an average of 2-7 goods and CBD oils with a concentration of 3%-5% (30-50 mg/mL) CBD. The majority (n/N = 10/16, 62.5%) displayed potential health-related benefits indirectly on their website, and in the case of one web shop (n/N = 1/16, 6.3%), we detected COVID-19-related use. Altogether, 30 types of purported "indications" were collected. A total of 12 CBD oil products were test-purchased from online retailers in December 2020. Upon evaluating the packaging and product information, we noticed that three products (n/N = 3/12, 25%) lacked instructions on use, hence increasing the risk of inappropriate application and dosing. The cannabidiol content was quantified using UHPLC. The measured CBD concentrations of the products ranged from 19.58 mg/mL to 54.09 mg/mL (mean 35.51 mg/mL, median 30.63 mg/mL, and SD ± 12.57 mg/mL). One (8.33%) product was underlabeled, five (41.67%) were over-labeled, and only every second product (50%) was appropriately labeled based on the quantitative assessment of CBD concentration. Discussion: Further research and quality control are necessary to establish the regulatory context of the usage and classification of CBD and other cannabinoids in nonmedicinal products (e.g., food supplements), as authorities and policymakers worldwide struggle with the uncertainties surrounding CBD products.

Analysis of pharmacovigilance databases for spontaneous reports of adverse drug reactions related to substandard and falsified medical products: A descriptive study.

Introduction: The public health threat of substandard and falsified medicines has been well known in the last two decades, and several studies focusing on the identification of products affected and preventing consumption have been published. However, the number of these products reaching patients and causing health consequences and adverse drug reactions is not a well-researched area. Objectives: Our aim was to identify and describe the characteristics of cases that are related to adverse drug reactions potentially originating from counterfeit medication using publicly available pharmacovigilance data. Methods: A descriptive study was performed based on pharmacovigilance data retrieved from Individual Case Safety Reports (ICSRs) identified in the European Medicines Agency's EudraVigilance and FDA Adverse Event Reporting System (FAERS) databases in April 2022 using selected MedDRA preferred terms: counterfeit product administered, product counterfeit, product label counterfeit, product packaging counterfeit, suspected counterfeit product, adulterated product, product tampering, and suspected product tampering. ICSRs were analyzed by age and gender, by year of reporting, region of origin, reporter's profession, and severity of the outcome. The disproportionality method was used to calculate pharmacovigilance signal measures. Results: A total of 5,253 cases in the FAERS and 1,049 cases in the EudraVigilance database were identified, generally affecting middle-aged men with a mean age of 51.055 (±19.62) in the FAERS and 64.18% of the cases between 18 and 65 years, while the male to female ratios were 1.18 and 1.5. In the FAERS database, we identified 138 signals with 95% confidence interval including sildenafil (n = 314; PRR, 12.99; ROR, 13.04; RRR, 11.97), tadalafil (n = 200; PRR, 11.51; ROR, 11.55; RRR, 10.94), and oxycodone (n = 190; PRR, 2.47; ROR, 2.14; RRR, 2.47). While in the EV data 31, led by vardenafil (n = 16, PRR = 167.19; 101.71-274.84; 95% CI, RRR = 164.66; 100.17-270.66; 95% CI, ROR = 169.47; 103.09-278.60; 95% CI, p < 0.001), entecavir (n = 46, PRR = 161.26, RRR = 154.24, ROR = 163.32, p < 0.001), and tenofovir (n = 20, PRR = 142.10, RRR = 139.42, ROR = 143.74, p < 0.001). Conclusion: The application of pharmacovigilance datasets to identify potential counterfeit medicine ADRs can be a valuable tool in recognition of potential risk groups of consumers and the affected active pharmaceutical ingredients and products. However, the further development and standardization of ADR reporting, pharmacovigilance database analysis, and prospective and real-time collection of potential patients with health consequences are warranted in the future.

Prospective Risk Assessment of Medicine Shortages in Europe and Israel: Findings and Implications.

INTRODUCTION: While medicine shortages are complex, their mitigation is more of a challenge. Prospective risk assessment as a means to mitigate possible shortages, has yet to be applied equally across healthcare settings. The aims of this study have been to: 1) gain insight into risk-prevention against possible medicine shortages among healthcare experts; 2) review existing strategies for minimizing patient-health risks through applied risk assessment; and 3) learn from experiences related to application in practice. METHODOLOGY: A semi-structured questionnaire focusing on medicine shortages was distributed electronically to members of the European Cooperation in Science and Technology (COST) Action 15105 (28 member countries) and to hospital pharmacists of the European Association of Hospital Pharmacists (EAHP) (including associated healthcare professionals). Their answers were subjected to both qualitative and quantitative analysis (Microsoft Office Excel 2010 and IBM SPSS Statistics®) with descriptive statistics based on the distribution of responses. Their proportional difference was tested by the chi-square test and Fisher's exact test for independence. Differences in the observed ordinal variables were tested by the Mann-Whitney or Kruskal-Wallis test. The qualitative data were tabulated and recombined with the quantitative data to observe, uncover and interpret meanings and patterns. RESULTS: The participants (61.7%) are aware of the use of risk assessment procedures as a coping strategy for medicine shortages, and named the particular risk assessment procedure they are familiar with failure mode and effect analysis (FMEA) (26.4%), root cause analysis (RCA) (23.5%), the healthcare FMEA (HFMEA) (14.7%), and the hazard analysis and critical control point (HACCP) (14.7%). Only 29.4% report risk assessment as integrated into mitigation strategy protocols. Risk assessment is typically conducted within multidisciplinary teams (35.3%). Whereas 14.7% participants were aware of legislation stipulating risk assessment implementation in shortages, 88.2% claimed not to have reported their findings to their respective official institutions. 85.3% consider risk assessment a useful mitigation strategy. CONCLUSION: The study indicates a lack of systematically organized tools used to prospectively analyze clinical as well as operationalized risk stemming from medicine shortages in healthcare. There is also a lack of legal instruments and sufficient data confirming the necessity and usefulness of risk assessment in mitigating medicine shortages in Europe.

Developing a framework regarding a complex risk based methodology in the evaluation of hazards associated with medicinal products sourced via the internet.

Today, the increasing number of illicit internet pharmacies is a global phenomenon, however, the size of the online pharmaceutical market is still relatively unknown and the dubious quality of products is questionable and warrants investigation. Descriptive data from this black market channel are derived from studies analyzing the online availability of different medications procured over the internet and their methodology is quite heterogeneous. Our aim was to develop a comprehensive and specific risk assessment for selecting high patient safety risk medications from the online pharmaceutical market. A rapid tool was developed based upon the two quality and safety standard resolutions in pharmaceutical practice, published by the European Directorate for the Quality of Medicines, and was illustrated on eye drops. We developed five dimensions in support of the risk assessment including intrinsic, extrinsic and potential risks of counterfeiting. The five criteria were integrated in a comprehensively weighted risk-scoring format. The probability of procuring the product from the internet was also assessed based on the number of relevant links within the first twenty search engine results and the cost of the products. With the application of the tool a dorzolamide & timolol combination eye drop represented the highest overall patient safety risk score. In consideration of our literature review of the past 20 years, there is no current, standardized methodology to effectively identify pharmaceutical products associated with high patient safety risks. Notably, the fully comprehensive analysis of the internet pharmaceutical market and the test purchase of all online available medicines is unrealistic. Therefore, we developed a method to aid online surveillance researches and targeted international organizational led joint actions against the uncontrolled sale of falsified and substandard medications (e.g.: Operation Pangea).

Dietary quercetin supplements: Assessment of online product informations and quantitation of quercetin in the products by high-performance liquid chromatography.

Administration of the increasingly popular dietary supplements containing quercetin may interfere with drug therapy. We intended to evaluate the online availability and quercetin content of the high-dose mono-component quercetin products and to review the potential use of quercetin products and their interactions with drugs. We monitored the online access to quercetin-containing dietary supplements, collected the relevant information from the websites, procured selected products from the vendors, and subjected them to substance analysis. The quercetin content was quantified by an HPLC-UV method. Twenty-five websites offered mono-component quercetin products, and nine products were procured. The quercetin content of eight products differed only ±10% from the nominal dose, whereas one product contained almost 30% more quercetin. Misleading indications such as antitumor and cardiovascular effects were often found on the sellers' websites. Quercetin-containing dietary supplements are available online with misleading indications. The recommended daily doses are often high (occasionally over 1,000 mg), which may induce clinically relevant interactions with medications. Because high-quercetin content of dietary supplements was confirmed, health care professionals should be aware of the unregulated internet market of dietary supplements and should consider the interactions of these substances with drugs.

A challenge for healthcare but just another opportunity for illegitimate online sellers: Dubious market of shortage oncology drugs.

INTRODUCTION: Drug shortages mean a challenge to healthcare systems. Exposed patients or health care providers may seek alternative resources for these products online. The purpose of our study was to analyze the online availability of oncology shortage drugs at national and at international levels in 2014 and 2016. METHODS: We tested the online accessibility of oncology shortage drugs by simulating the Internet search method of patients. Search results were evaluated according to operational, distributional, and patient safety characteristics. RESULTS: In 2014 and 2016 all (100%) antineoplastic agents affected by shortages were available on the Internet without medical prescription. The number of relevant websites among search engine results has decreased from 112 to 98, while online vendors actually offering oncology shortage drugs for sale has risen from 66.1% to 80.6% within relevant websites in the two evaluated years. None of the online sellers were classified as legitimate or accredited by LegitScript and VIPPS online pharmacy verification databases. CONCLUSION: According to our findings shortage oncology drugs are widely available online. To manage shortages and illegal Internet trade national and international standardized shortage reporting and information systems, regularly updated Internet pharmacy verification databases are needed. As well, institutional procurement and medication use review policies are required.

Consumers Turning to the Internet Pharmacy Market: Cross-Sectional Study on the Frequency and Attitudes of Hungarian Patients Purchasing Medications Online.

BACKGROUND: During the past two decades, the internet has become an accepted way to purchase products and services. Buying medications online are no exception. Besides its benefits, several patient safety risks are linked to the purchase of medicines outside the traditional supply chain. Although thousands of internet pharmacies are accessible on the web, the actual size of the market is unknown. Currently, there is limited data available on the use of internet pharmacies, the number, and attitude of people obtaining medications and other health products from the internet. OBJECTIVE: This study aims to gather information on the frequency and attitudes of patients purchasing medications online in a nationally representative sample of outpatients. Attitudes towards main supply chain channels, perceived benefits, and disadvantages of influencing online medication purchase are evaluated. METHODS: A cross-sectional explorative study using a personally administered survey was conducted in a representative sample of Hungarian outpatients in 2018. RESULTS: A total of 1055 outpatients completed the survey (response rate 77.23%). The mean age was 45 years, and 456 (43.22%) reported having chronic health conditions. The majority (872/1055, 82.65%) of the respondents were aware that medications could be obtained online, but only 44 (4.17%) used the internet for previous medication purchases. Attitudes towards the different pharmaceutical supply chain retail channels showed significant differences (P<.001), respondents accepted retail pharmacy units as the most appropriate source of medications while rejected internet pharmacies. Respondents were asked to evaluate 9 statements regarding the potential benefits and disadvantages about the online medicine purchase, and based on the computed relative attitude rate there is a weak still significant tendency toward rejection (P<.001). Correspondence of demographic factors, internet usage behavior, and prospective online drug purchase attitude was evaluated. Respondents who use the internet more and purchase goods online will be more likely to buy medications online. Furthermore, youth and education will determine the medication purchase behavior. CONCLUSIONS: Many patients will purchase medications on the internet in the future. Currently, there is an increased risk of patients buying products from illegal sites because these dominate the global online pharmacy market. Consequently, improved patient-provider communication and promotion campaigns are needed to inform the public about the safe use of internet pharmacies, as these initiatives can directly prevent patient safety threats.

Availability and quality of illegitimate somatropin products obtained from the Internet.

Background Growth hormones are widely available on the Internet for those who want to enhance their physical performance and improve body satisfaction. Illegitimate websites market somatropin injections without medical prescription and encourage misuse. Customers potentially put their health at risk when purchasing parenteral medications online. Objective The objective of our study was to evaluate the online market of no-prescription somatropin products and to analyse and document Internet pharmacy characteristics, distribution and pharmaceutical quality. Setting Websites indexed in Google promoting somatropin for sale direct to patients. Method Websites promoting the sale of growth hormone products were identified and analysed from June to August 2014. Internet vendor sites were evaluated to identify possible patient and medication safety concerns. Website characteristics, delivery time, storage conditions, packaging and attached product information were assessed. Investigation of the somatropin content was achieved using capillary electrophoresis with UV detection and electrospray ionization mass spectrometry. Main outcome measure Accessibility and quality of somatropin injections. Results Seventeen individual Internet vendor websites distributed somatropin products directly to patients, majority (94%) did not require a valid medical prescription before dispensing the products. Majority (70%) of Internet pharmacies displayed no medical information and none (0%) of the vendors displayed any regulatory body logo. All online samples had significantly (p < 0.001) lower somatropin concentration than labelled. Conclusion Our results clearly illustrate that prescription only biologic drugs are widely available online and can be easily accessed by anyone. Unprofessional distribution and handling is likely to cause degradation and possible patient safety concerns.

[Comprehensive evaluation of drug interaction screening programs: discrepancies and concordances]. / Gyógyszerkölcsönhatások kiszurésére szolgáló adatbázisok értékelése: ellentmondások és egyezoségek.

INTRODUCTION: Recognition of potentially harmful drug interactions is one of the duties of healthcare. However, solutions involving databases are fraught with contradictions due to the lack of standardized principles and data. AIM: The aims of the authors were to perform a comparative evaluation of Hungarian and international databases and to explore ambiguities and contradictions in order to develop more standardized criteria for screening interactions. METHOD: Four Hungarian and two English-language websites and software, and the summaries of product characteristics were compared. The authors analyzed 40 drug-drug and 8 drug-supplement interactions and looked at 8 cases, which represent 28 pairs of interacting substances. RESULTS: The databases warn about most interactions, but these warnings were rarely helpful in preventing undesired consequences. The authors found discrepancies between the databases in 70% of interactions. When looking at different products with the same active ingredients, discrepancies cropped up in 0-66.7% of the cases. Up to 80% of searches for supplementary product interactions did not produce satisfactory results. CONCLUSIONS: In the present situation mapping these ambiguities and creating a standardized classification system would be advantageous.

Identification and evaluation of drug-supplement interactions in Hungarian hospital patients.

BACKGROUND: The increasing number of patients taking supplementary products together with prescribed medicines has become a new challenge for health care systems. These products may influence therapy outcomes by inducing unwanted effects. Particularly concerning is the potential for harmful interactions between prescribed medicines and supplementary products. OBJECTIVE: The aims of the study were to evaluate supplement use, to identify and analyse potential interactions, and to assess the efficiency of computerised interaction screening. SETTING: Participants of the study were inpatients and outpatients of a Hungarian university hospital. METHOD: A cross-sectional point-of-care survey of 200 patients was carried out. Data was collected through personal interviews and a review of the medical records. Drug-drug, drug-supplement and supplement-supplement interactions were analysed with three interaction databases (Lexi-Interact Online, Medscape Drug Interaction Checker and Mediris). MAIN OUTCOME MEASURE: Prevalence of supplementary product use, number of medicines and supplementary products per patient, procurement sources of products, number of potentially severe interactions. RESULTS: There was a marked difference between data obtained from patient interviews and the medical records. 85.5 % of the surveyed patients took supplementary products during the 2 weeks prior to the interview. The average number of prescribed medicines and supplementary products were 7.8 and 2.5, respectively. Women were more likely to take supplements than men. There was no significant difference in supplement use between patients under or over 60 years, between inpatients and outpatients and among patients in various wards. 39.4 % of supplementary products were purchased outside a regulated pharmacy environment. Potentially severe drug-supplement interactions were detected with 45.2 % of supplement users; however the majority of interactions were not included in one or the other of the three databases. In addition to that the risk ratings of the same interactions varied greatly between databases. CONCLUSION: A significant number of patients are exposed to potential drug interactions with supplementary products; however interagreement among interaction databases is poor. Our data suggest that a full medication history should specifically address the intake of supplements.