Undesirable Drug Interactions Research Articles

Breast Cancer Resistance Protein: Structure, Localization, Functions, Significance for Rational Pharmacotherapy

INTRODUCTION: Currently, investigation of efflux transport systems of an organism is an important scientific and practical task permitting to more deeply investigate the pharmacokinetics of medical drugs and to optimize pharmacotherapy of a number of diseases. The super family of ABC transporters plays a significant role in transport of biobiotics, the processes of absorption, distribution and excretion of medical drugs from an organism, in realization of undesired drug-drug interactions and development of pharmacoresistance. An important representative of this super family is breast cancer resistance protein (BCRP). AIM: Systematization of the data on BCRP structure, localization, functions, substrates and modulators of its activity. This literature review presents modern data on the molecular and spatial structure of BCRP, its localization in the cell, in organs and tissues. The data from studies of the functions of BCRP in an organism, of its role in the development of undesired drug-drug interactions at different stages of pharmacokinetics are summarized. An up-to-date list of medicinal drugs that are substrates and inhibitors of BCRP is given. Modern approaches to testing medical drugs for belonging to BCRP substrates or modulators of its activity are disclosed. CONCLUSION: The significance of BCRP consists in the existence of a wide range of drugs that are its substrates or modulators of its activity. Upon that, of increasing significance is the investigation both of new and long-known medicinal substances for their belonging to substrates, inducers or inhibitors of breast cancer resistance protein, in order to increase the effectiveness of pharmacotherapy and reduce the risk of undesired drug interactions. Search for non-drug substrates and modulators of BCRP activity permits to obtain new markers for conducting effective studies of safe pharmacokinetics both in vitro and in vivo.

#1408 Dehydration cannot substitute for any of the triple whammy drugs to cause acute kidney injury

Abstract Background and Aims Polymedication in patients with chronic diseases, such as hypertension, can lead to undesired drug interactions. The combination of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) with diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) can cause triple whammy (TW)-induced acute kidney injury (TW-AKI). Up to 9% of hypertensive patients used NSAIDs in combination with ACEIs / ARBs and diuretics. AKI has a mortality rate of 40% and TW increases the risk of AKI by 30% compared to the combination of only two drugs. In addition, TW-AKI is associated with other risk factors such as dehydration, which may exacerbate the injury. Consequently, the aim of our study was to determine whether dehydration combined with two of the TW drugs could induce AKI in an in vivo experimental model. Method Three months old male Spontaneously Hypertensive Rats (SHR) were divided into four experimental groups: control group (CT); TW group (TW), which received four days of double therapy with trandolapril and furosemide, followed by a triple therapy for two days with trandolapril, furosemide and ibuprofen; trandolapril and ibuprofen group (T+I), which received four days of trandolapril followed by two days of trandolapril and ibuprofen; furosemide and ibuprofen group (F+I), which received four days of furosemide followed by two days of furosemide and ibuprofen; and trandolapril and furosemide group (T+F), which received six days of trandolapril and furosemide. All groups were subjected to a 60-70% water restriction of basal intake (i.e. 15 mL/day) to generate mild dehydration. Blood and urine samples were collected at baseline (B), day 4 and day 6. Blood pressure was measured at baseline and day 4. Renal function was assessed by plasma creatinine, plasma urea and creatinine clearance, and hydration status was determined by plasma osmolarity and water balance (i.e. water intake minus urine flow). Results Under basal conditions, all rats were hypertensive. The combination of trandolapril and furosemide significantly reduced the mean blood pressure on day 4 (p = 0.0066), while trandolapril or furosemide alone did not achieve these decreases. After four days of water restriction to 15 mL/day, all groups showed mild dehydration with a decrease in water balance and an increase in plasma osmolarity by. Plasma creatinine and plasma urea values were only increased on day 6 in the TW group (p = 0.0009 and p = 0.02, respectively). Creatinine clearance was also clearly reduced in the TW group (p = 0.0004). F+I and T+F groups showed slight decreases in creatinine clearance at day 6, as well as slight increases in plasma urea. However, these changes were not as pronounced as those observed in the TW group. Conclusion In our in vivo model of TW-AKI, mild dehydration cannot replace any of the TW drugs, although it appears that combination of F+I and T+F in dehydrated rats slightly alter plasma urea and creatinine clearance values at day 6, suggesting that this condition maintained over time might lead to the development of AKI. Funding This research was funded by grants from Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación (PI21/01226 and PI21/00548 co-funded by the European Union; and RICORS2040, RD21/0005/0004, co-funded by the European Union—NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR)) and from Consejería de Educación, Junta de Castilla y León (IES160P20), co-funded by FEDER funds. Noelia Diaz-Morales is recipient of a Juan de la Cierva-Formación postdoctoral contract (FJC2020-043205-I) funded by MCIN/AEI/10.13039/501100011033 and the European Union “NextGenerationEU/PRTR”. Eva M. Baranda-Alonso is recipient of a predoctoral fellowship from the Junta de Castilla y Leon (Spain) and the European Social Fund from the European Commission.

Pasien Infark Miokard Akut pada Studi Penggunaan Obat Anti Platelet di RSUD Gambiran Kota Kediri

The purpose of this study was to determine the pattern of drug use, potential interactions, and side effects of antiplatelet drugs in acute myocardial infarction patients in inpatient installations to reduce morbidity and mortality rates at Gambiran Hospital, Kediri City. This study is a non-experimental study with descriptive research design and retrospective data collection, data collection using purposive sampling method. Retrospective data collection based on medical record data of patients with acute myocardial infarction, this research was conducted from January to December 2020, so that the pattern of use of anti-platelet drugs in patients with acute myocardial infarction was a combination of aspirin 80 mg 1x1 with clopidogrel 75mg 1x1 (93%), with the route of drug administration orally. Analysis of potential drug interactions was carried out using the Drugs Interaction Checker and obtained 4 occurrences of major potential interactions and 10 occurrences of moderate potential interactions. The desired potential drug interaction was to prevent platelet aggregation. There was an undesirable potential drug interaction related to decreased antihypertensive effect of the drug, while potential drug interactions in the form of gastrointestinal bleeding and decreased renal function could not be determined.

Antibiotic Drug Interaction in Prescribing Asthma Patients in One of the Clinics in the Surabaya Area

Drug interactions are interactions that can occur if the effects of a drug are changed by other drugs, food or drinks. The aim of this research is to determine the potential for interactions between antibiotics and other drugs prescribed to asthma patients. Antibiotics are the drugs most widely used for infections caused by bacteria. Determining the mechanism of potential interactions between antibiotics and other drugs prescribed to asthma patients in this study using the Medscape application. The research results showed that there were 2044 prescriptions for the period Juli - December 2022, which provided the highest potential for drug interactions, namely interactions with pharmacokinetic mechanisms in the metabolic phase with 69 incidents (20.47%). Meanwhile, the highest level of severity was monitoring closely, 291 (86.35%) and those with the potential for serious interactions were 46 incidents (13.65%). In this research, the active role of Pharmacy Technicians and Pharmacists is needed to monitor the use of drugs that have the potential to cause drug interactions with prescribing doctors in the hope that undesirable drug interactions can be avoided.

Oral medicine administration errors in a patient with an enteral feeding tube

Proper nutrition is vital for all patients with an expected lifespan. It is strongly recommended that patients whose oral intake is impaired or suspected to be impaired should be provided nutritional support. Concurrent medication administration during enteral nutrition may result in complications unless necessary precautions are taken. This study presents a case of a 94-year-old male patient with poor general health condition and being treated in a palliative care service. The patient was fed with an enteral feeding tube for seven drugs. There have been two tube occlusions causing the replacement of the tube since the enteral feeding tube was placed.The clinical pharmacist checked how the patient’s drugs were given through a nasogastric tube and how the patient’s relatives administered the drugs. Inappropriate dosage form selections and errors in administration through the nasogastric tube were identified. The interaction and incompatibility of the patient’s medications with the nutritional formula were also investigated. The clinical pharmacist informed the person giving the medicine to the patient about the correct administration of the medicine from the tube. The proper method for administering medications from the tube was ensured accordingly. Following the clinical pharmacist’s training, it was observed that the nasogastric tube was correctly used to administer the drug and the patient being monitored had no tube obstruction in the later phases of the treatment.It may be beneficial for a pharmacist to review drug dosage forms and applications in patients with a feeding tube in order to ensure correct administration and avoid undesired drug interactions.

Risk of Polypharmacy and Its Outcome in Terms of Drug Interaction in an Elderly Population: A Retrospective Cross-Sectional Study.

The simultaneous use of multiple drugs-termed 'polypharmacy'-is often required to manage multiple physiological and biological changes and the interplay between chronic disorders that are expected to increase in association with ageing. However, by increasing the number of medications consumed, the risk of undesirable medication reactions and drug interactions also increases exponentially. Hence, knowledge of the prevalence of polypharmacy and the risk of potentially serious drug-drug interactions (DDIs) in elderly patients should be considered a key topic of interest for public health and health care professionals. Methods: Prescription and demographic data were collected from the electronic files of patients who were aged ≥ 65 years and attended Al-Noor Hospital in Makkah, Saudi Arabia, between 2015 and 2022. The Lexicomp® electronic DDI-checking platform was used to evaluate the patients' medication regimens for any potential drug interactions. Results: A total of 259 patients were included in the study. The prevalence of polypharmacy among the cohort was 97.2%: 16 (6.2%) had minor polypharmacy, 35 (13.5%) had moderate polypharmacy, and 201 (77.6%) had major polypharmacy. Of the 259 patients who were taking two or more medications simultaneously, 221 (85.3%) had at least one potential DDI (pDDI). The most frequently reported pDDI under category X that should be avoided was the interaction between clopidogrel and esomeprazole and was found in 23 patients (18%). The most frequently reported pDDI under category D that required therapeutic modification was the interaction between enoxaparin and aspirin, which was found in 28 patients (12%). Conclusions: It is often necessary for elderly patients to take several medications simultaneously to manage chronic diseases. Clinicians should distinguish between suitable, appropriate and unsuitable, inappropriate polypharmacy, and this criterion should be closely examined when establishing a therapeutic plan.

Treatment of Tuberculosis and the Drug Interactions Associated With HIV-TB Co-Infection Treatment

Tuberculosis (TB) is a communicable disease that is a major source of illness, one of the ten causes of mortality worldwide, and the largest cause of death from a single infectious agent Mycobacterium tuberculosis. HIV infection and TB are a fatal combination, with each speeding up the progression of the other. Barriers to integrated treatment as well as safety concerns on the co-management of HIV- TB co-infection do exist. Many HIV TB co-infected people require concomitant anti-retroviral therapy (ART) and anti-TB medication, which increases survival but also introduces certain management issues, such as drug interactions, combined drug toxicities, and TB immune reconstitution inflammatory syndrome which has been reviewed here. In spite of considerable pharmacokinetic interactions between antiretrovirals and antitubercular drugs, when the pharmacological characteristics of drugs are known and appropriate combination regimens, dosing, and timing of initiation are used, adequate clinical response of both infections can be achieved with an acceptable safety profile. To avoid undesirable drug interactions and side effects in patients, anti TB treatment and ART must be closely monitored. To reduce TB-related mortality among HIV-TB co-infected patients, ART and ATT (Anti Tuberculosis Treatment) outcomes must improve. Clinical practise should prioritise strategies to promote adherence, such as reducing treatment duration, monitoring and treating adverse events, and improving treatment success rates, to reduce the mortality risk of HIV-TB co-infection.

Гастроэзофагеальная рефлюксная болезнь и коррекция ее проявлений у пациентов перед офтальмохирургическими вмешательствами

Purpose. Evaluation of the frequency of extraesophageal manifestations in the structure of gastroesophageal reflux disease (GERD) in patients admitted for ophthalmic surgery. Material and methods. The preoperative state of 76 patients with extraesophageal manifestations of GERD was analyzed. The assessment of the adequacy and effectiveness of drug therapy, algorithms for diagnosing extraesophageal manifestations of GERD is given, our own clinical case is presented to illustrate the complexity of diagnosing extraesophageal manifestations of GERD. Results. A group of 76 people with extraesophageal manifestations of GERD (21 %) out of 363 patients with GERD admitted for treatment in 2019 was studied. In 25 people (33 %), the extraesophageal form of GERD was not diagnosed before admission to the hospital. Of these, in 17 people GERD proceeded under the guise of cardiological pathology, in 8 people - under the guise of bronchopulmonary pathology. Conclusion. GERD occupies a leading position among diseases of the upper gastrointestinal tract (more than 30 %). About 21 % are atypical manifestations of GERD. Modern etiopathogenetic treatment of GERD makes it possible to effectively stop the symptoms of the disease, avoid polypharmacy, undesirable drug interactions and unreasonable refusal of planned surgical treatment for patients with ophthalmic diseases. Keywords: gastroesophageal reflux disease, extraesophageal manifestations, cardiological and bronchopulmonary “masks”, ophthalmic surgery.

Social and economic factors associated with antidepressant use: Results of a national survey in primary care

• The findings suggested inequity in access to drug treatment for depression in a middle-income country, especially for non-white individuals and those from lower social economic status brackets. • Public policies should be developed on primary health care services to optimize the detection and treatment of depression. • Polypharmacy was strongly associated to use of antidepressants. • Optimizing pharmacotherapy can minimize harm and undesired drug interactions. Background: Antidepressants are widely prescribed, and it is important to describe their use characteristics. We aimed to estimate the prevalence of antidepressant use and identify associated factors in a cross-sectional study from a middle-income country. Methods: Participants (n=8,803) from the National Survey on Access, Use, and Promotion of the Rational Use of Medicines in Brazil, a cross-sectional study with a representative sample, were asked about the use of any medicines in the past 30 days. Through the answers, we classified the antidepressants users and non-users. The association between antidepressant use, demographic and clinical characteristics was evaluated. Results: The prevalence of antidepressant use was 6.8% (95% CI 6.2 - 7.3). Most users whom self-reported a previous diagnosis of depression (70.6%) did not report antidepressant use, suggesting underuse. Fluoxetine and amitriptyline ranked first in use. White females, from higher economic status, self-reporting a previous diagnosis of depression, in polypharmacy and in use of psychotropics, with alcohol abstinence, were more likely to use the medicines. Limitations: The use of drugs was measured by self-report, which might have underestimated results. Indication for antidepressant use in depression or other conditions was not investigated. Conclusions: The prevalence of antidepressant use observed in Brazil is lower than in the USA and some European countries. Although patients have a universal right to health in Brazil, improved primary care actions are required to ensure access to treatment of depressive disorders, especially for non-white individuals and those from lower social-economic status brackets.

Inflammation, impaired motor function and visceral hypersensitivity: the main mechanisms of functional disorders of the gastrointestinal tract (materials of the Expert Council and literature review)

Aim. To review the main mechanisms of functional disorders of the gastrointestinal tract and to present the materials of an Expert Council, which was held on 10 December 2021 in Moscow.Key points. The pathogenesis of the most common functional diseases of the gastrointestinal tract — functional dyspepsia (FD) and irritable bowel syndrome (IBS) is multifactorial and includes motor disorders of various parts of the gastrointestinal tract, visceral hypersensitivity, changes in the intestinal microbiome, impairment of the permeability of the protective barrier, low-grade inflammation of the gastrointestinal mucosa, etc. This often leads to the prescription of a complex of various medications to such patients, which increases the risk of undesirable drug interactions and side effects. Multitargeted therapy involves the use of drugs that simultaneously affect different pathogenetic links. One of these drugs is Iberogast®, which normalizes gastrointestinal motility and visceral sensitivity, has an anti-inflammatory action and is highly effective in treatment of FD and IBS.Conclusion. In the treatment of functional gastrointestinal diseases characterized by multifactorial pathogenesis, preference should be given to multi-targeted therapy with the use of drugs that have an effect on its various links.

Drug Transporters ABCB1 (P-gp) and OATP, but not Drug-Metabolizing Enzyme CYP3A4, Affect the Pharmacokinetics of the Psychoactive Alkaloid Ibogaine and its Metabolites

The psychedelic alkaloid ibogaine is increasingly used as an oral treatment for substance use disorders, despite being unlicensed in most countries and having reported adverse events. Using wild-type and genetically modified mice, we investigated the impact of mouse (m)Abcb1a/1b and Abcg2 drug efflux transporters, human and mouse OATP drug uptake transporters, and the CYP3A drug-metabolizing complex on the pharmacokinetics of ibogaine and its main metabolites. Following oral ibogaine administration (10 mg/kg) to mice, we observed a rapid and extensive conversion of ibogaine to noribogaine (active metabolite) and noribogaine glucuronide. Mouse Abcb1a/1b, in combination with mAbcg2, modestly restricted the systemic exposure (plasma AUC) and peak plasma concentration (Cmax) of ibogaine. Accordingly, we found a ∼2-fold decrease in the relative recovery of ibogaine in the small intestine with fecal content in the absence of both transporters compared to the wild-type situation. Ibogaine presented good intrinsic brain penetration even in wild-type mice (brain-to-plasma ratio of 3.4). However, this was further increased by 1.5-fold in Abcb1a/1b;Abcg2 −/− mice, but not in Abcg2 −/− mice, revealing a stronger effect of mAbcb1a/1b in restricting ibogaine brain penetration. The studied human OATP transporters showed no major impact on ibogaine plasma and tissue disposition, but the mOatp1a/1b proteins modestly affected the plasma exposure of ibogaine metabolites and the tissue disposition of noribogaine glucuronide. No considerable role of mouse Cyp3a knockout or transgenic human CYP3A4 overexpression was observed in the pharmacokinetics of ibogaine and its metabolites. In summary, ABCB1, in combination with ABCG2, limits the oral availability of ibogaine, possibly by mediating its hepatobiliary and/or direct intestinal excretion. Moreover, ABCB1 restricts ibogaine brain penetration. Variation in ABCB1/ABCG2 activity due to genetic variation and/or pharmacologic inhibition might therefore affect ibogaine exposure in patients, but only to a limited extent. The insignificant impact of human CYP3A4 and OATP1B1/1B3 transporters may be clinically advantageous for ibogaine and noribogaine use, as it decreases the risks of undesirable drug interactions or interindividual variation related to CYP3A4 and/or OATP activity.

Evaluation of Potential Drug Interactions with AiDKlinik® in a Random Population Sample.

PurposeUndesirable drug interactions are frequent, they endanger the success of therapy, and they lead to adverse drug reactions. The present study aimed to evaluate statistically potentially drug interactions in a locally circumscribed, random sample population.Patients and MethodsIn a random sample population of 264 patients taking medications, we performed analyses with the drug information system AiDKlinik®. Statistical analysis was performed using SAS version 9.4.ResultsStatistically potentially drug interactions were recorded in 82/264 (31.1%) subjects, including 39/82 (47.56%) men, and 43/82 (52.43%) women (χ2= 0.081; p = 0.776). The average number of potential possible interactions detected per person was 1.60 ± 1.21. The regression model with the variables age, body-mass-index and number of long-term-medications shows a significant association between the number of long-term medications taken and the number of moderately severe and severe reactions to drug interactions (F(3.239) = 28.67, p < 0.0001; (t(239) 8.28; p < 0.0001)). After backward elimination, the regression model showed a significant interaction with the number of long-term medications (t (240) = 8.73, p < 0.0001) and body-mass-index (t (240) = 2.02, p = 0.0442). In descriptive analysis, the highest percentages of potential drug interactions occurred in 42/82 (51.22%) subjects with body mass indices (BMIs) >25 kg/m2 and in 28/82 (34.15%) subjects aged 61–70 years.ConclusionNumber of long-term medications use, age, and obesity may lead to increased drug–drug interactions in a random population sample.

PREVENTION AND MANAGEMENT OF RELAPSE OF ACUTE LEUKEMIA AND MYELODYSPLASTIC SYNDROME AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PEDIATRIC PATIENTS

The best way to manage acute leukemia relapse after HCT is to prevent it, buying time for GVL with immunomodulation and, if no GVHD between days +60 and + 90, prophylactic DLI can be indicate for very high or high risk patients. Short-term low dose of cyclosporine or methotrexate can add safety to pro-DLI, particularly after mismatched or unrelated transplantation. Maintenance with imatinib or dastinib, recommended for Ph-positive ALL, with sorafenib, for FLT3-ITD AML, or azacitidine, for myelodysplastic syndrome patients, can be effective in reducing relapse rates. However, target agent maintenance can add toxicity, depends on patient adherence and demands physician experience to know when is safe to start, how adjust the dose according individual tolerance after transplant and to detect undesirable drug interactions. The second step to avoid hematological relapse is preemptive approach guided by measurable residual disease or mixed chimerism. In patients off immunosuppression, chemotherapy followed by DLI is a useful strategy, and if no response, interferon alpha can be associated to enhance GVL. Target-specific agents can be start at this point either. After relapse, antigen-directed therapy with blinatumumab for CD19 ALL, inotuzumab for CD22 ALL are excellent options to induce MRD negativity and facilitate HCT. Disadvantages of new immunotherapies are: high incidence of VOD with inotuzumab and gemtuzumab; lower response in patients with high leukemia burden or concurrent extramedullary relapse; necessity of consolidation with HCT after a bridging therapy with BiTE and probably with CAR-T cell therapy also. It is important to realize that if remission after chemotherapy is associated with the development of GVHD, then there may be limited benefit (and possibly harm) in consolidating with any kind of cellular therapy. However, for patients who achieved remission without GVHD, either DLI or second transplant can be recommend. Further studies are necessary to determine at which point each strategy might yield the best results.

Anxiety and depression in COVID-19: treatment options

During the examination of post-COVID patients, a direct and indirect negative effect of COVID-19 on the nervous system is found. Among the mediated subjectively significant stress factors of the pandemic, a potential long-term threat to life, prolonged quarantine measures with selfisolation, lack of stable immunity, restriction of access to medical services, etc. are of particular importance. An increased frequency of depression (up to 53.5%), anxiety (up to 50.9%), and mixed anxiety/depressive disorders were reported during the pandemic. Psychopharmacotherapy in patients with COVID-19 should include drugs not only with minimally expressed undesirable effects and adverse drug interactions but also with the presence of additional therapeutic procognitive and somatotropic properties, similar to those identified in the antidepressant fluvoxamine.

COMPARATIVE ANALYSIS OF DRUG EFFICACY IN THE TREATMENT FOR COVID-19 SEVERE FORMS, BASED ON ATTRIBUTE-BASED STATISTIC METHODS AND ANALYSIS OF DRUG INTERACTIONS

Severe and critical forms of COVID-19 are beset by the development of “a cytokine storm”, which is characterized by an increased secretion of proinflammatory cytokines. Therefore, one of the leading strategies for treating patients with severe forms of COVID-19 is the reduction of concentration of proinflammatory cytokines and leveling out their effect on the patient. Among the drugs aimed at reducing the concentration of proinflammatory cytokines, IL-6 inhibitors, IL-1 inhibitors, JAK inhibitors and systemic glucocorticosteroids have been found useful in COVID-19. All of these drugs are currently prescribed off-label.The aimof the work is a comparative analysis of the data from the literature sources in the PubMed system, devoted to the clinical efficacy and safety of IL-6, IL-1, JAK inhibitors and systemic glucocorticosteroids in the treatment for severe forms of COVID-19.Materials and methods. In the treatment for severe forms of COVID-19, materials for the comparative analysis were the data from the literature sources in the PubMed system, on the studies devoted to the use of the systemic glucocorticosteroid dexamethasone, IL-6 inhibitor tocilizumab, IL-1 inhibitor anakinra, and JAK inhibitor ruxolitinib. The analysis was performed by statistical evaluation of the drugs effect within the 28-day survival rate among the patients with severe COVID-19. Attributive statistics was used as a statistical tool. The safety of the drug use was assessed by analyzing potential drug interactions. The information about potential drug interactions, was obtained from a specialized website – Drugs.com. Knowmore. Besure (https://www.drugs.com/interaction/list/).Results. As a result of the analysis, it has been established that tocilizumab has the highest efficacy rates. In this respect, it is followed by dexamethasone. The attributive efficacy rates and 95% confidence interval values for the both drugs were statistically significant. The indices of relative and population attributive kinds of efficacy, were also higher for tocilizumab, but a 95% confidence interval of these indices, get into the range of statistically insignificant values, requiring additional evidence of their efficacy. According to the data obtained, tocilizumab efficacy is higher than that of the other drugs compared: NNT (dexamethasone) – 32; NNT (tocilizumab) – 4, NNT (ruxolitinib) – 7; NNT (anakinra) – 35.Conclusion. The choice of a drug should be based on the patient’s condition, comorbidities, and medications used in therapy to minimize the risk of undesirable drug interactions. Against the background of the lowest efficacy among the compared drugs, a high efficacy for the patients with concomitant hepatobiliary disorders and DIC syndrome, has been established for the inhibitor IL-1 anakinra, which makes it the drug of choice among the patients with these diseases and under these conditions in the development of “a cytokine storm”.

Astenic disorders within the framework of post-covid syndrome

The direct neurotropic and neurotoxic effect of the SARS-CoV-2 virus on the central nervous system, as well as the stressful effect of various factors of the COVID-19 pandemic, contribute to the development of the so-called post-COVID syndrome. The clinical picture of the syndrome includes asthenic, anxiety-asthenic, and depressive manifestations. When prescribing psychopharmacotherapy to patients who have undergone COVID-19, it is recommended to assess the potential benefits and risks in the aspect of using drugs not only with therapeutic antiasthenic and anxiolytic properties, but with minimally expressed undesirable effects and adverse drug interactions.

Pharmacist Identification of Medication Therapy Problems Involving Cognition Among Older Adults Followed by a Home-Based Care Team.

Dementia, depression, and delirium alone or in combination (3Ds) can threaten independence among older adults, and polypharmacy may further accelerate decline. Clinical pharmacists can play an important role on multidisciplinary home-based care teams by identifying medication therapy problems (MTPs) involving cognition. Within a larger ongoing clinical trial, this paper describes cognition-related MTPs and pharmacist recommendations among older adults with 3Ds followed by a home-based care team. We conducted a retrospective analysis of medication data among Medicare Advantage members aged ≥65 years living at home in Connecticut with International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes related to 3Ds; analyses include the first 105 subjects randomized to thehome-based care team from March 2017 to January 2019. Advanced practice registered nurses conducted in-home medication reconciliations along with medical and cognitive assessments. Clinical pharmacists then conducted medication reviews centered on agents treating or exacerbating 3Ds. After review by the study advanced practice registered nurse, geriatrician, and psychiatrist, salient recommendations were forwarded to primary care providers for consideration. Medication therapy problems related to cognition were retrospectively abstracted and classified as: (1) indication: underuse or overuse; (2) effectiveness: ineffective agent or low dose (mainly for antidepressants); and (3) safety: undesirable effect (e.g., impaired cognition, dementia treatment side effects), unsafe medication (e.g., potentially inappropriate medications that can harm cognition), drug interaction, or high dose. Pharmacists identified 166 cognitive MTPs, with a mean (standard deviation) of 1.58 (1.35) [range 0-6] MTPs per subject. Indication MTPs represented 34% of total MTPs, of which 79% involved underuse and 21% overuse; effectiveness represented 13% of total MTPs; and safety represented over half (52%) of all MTPs, with benzodiazepines and anticholinergics frequently implicated. Recommendations commonly included medication reduction (discontinuation 23% and dose reduction 19%). We found MTPs involving cognition among most (79%) patients. Our study findings support the role of pharmacists on multidisciplinary teams to identify cognitively harmful medications, dementia treatment side effects, and untreated cognitive conditions. ClinicalTrials.gov NCT02945085.

The development of a targeted and more potent, anti-Inflammatory derivative of colchicine: Implications for gout

BackgroundColchicine is routinely used for its anti-inflammatory properties to treat gout and Familial Mediterranean fever. More recently, it was also shown to be of therapeutic benefit for another group of diseases in which inflammation is a key component, namely, cardiovascular disease. Whilst there is considerable interest in repurposing this alkaloid, it has a narrow therapeutic index and is associated with undesirable side effects and drug interactions. We, therefore, developed a derivatives of colchicine that preferentially target leukocytes to increase their potency and diminish their side effects. The anti-inflammatory activity of the colchicine derivatives was tested in experimental models of neutrophil activation by the etiological agent of gout, monosodium urate crystals (MSU). MethodsUsing a rational drug design approach, the structure of colchicine was modified to increase its affinity for βVI-tubulin, a colchicine ligand preferentially expressed by immune cells. The ability of the colchicine analogues with the predicted highest affinity for βVI-tubulin to dampen neutrophil responses to MSU was determined with in vitro assays that measure MSU-induced production of ROS, release of IL-1 and CXCL8/IL-8, and the increase in the concentration of cytoplasmic calcium. The anti-inflammatory property of the derivatives was assessed in the air pouch model of MSU-induced inflammation in mice. ResultsThe most effective compound generated, CCI, is more potent than colchicine in all the in vitro assays. It inhibits neutrophil responses to MSU in vitro at concentrations 10–100-fold lower than colchicine. Similarly, in vivo, CCI inhibits the MSU-induced recruitment of leukocytes at a 10-fold lower concentration than colchicine when administered prior to or after MSU. ConclusionsWe provide evidence that colchicine can be rendered more potent atinhibiting MSU-induced neutrophil activation and inflammation using a rational drug design approach. The development of compounds such as CCI will provide more efficacious drugs that will not only alleviate gout patients of their painful inflammatory episodes at significantly lower doses than colchicine, but also be of potential therapeutic benefit for patients with other diseases treated with colchicine.

Discovering instance and process spanning constraints from process execution logs

Instance spanning constraints (ISC) are the instrument to establish controls across multiple instances of one or several processes. A multitude of applications crave for ISC support. Consider, for example, the bundling and unbundling of cargo across several instances of a logistics process or dependencies between examinations in different medical treatment processes. Non-compliance with ISC can lead to severe consequences and penalties, e.g., dangerous effects due to undesired drug interactions. ISC might stem from regulatory documents, extracted by domain experts. Another source for ISC are process execution logs. Process execution logs store execution information for process instances, and hence, inherently, the effects of ISC. Discovering ISC from process execution logs can support ISC design and implementation (if the ISC was not known beforehand) and the validation of the ISC during its life time. This work contributes a categorization of ISC as well as four discovery algorithms for ISC candidates from process execution logs. The discovered ISC candidates are put into context of the associated processes and can be further validated with domain experts. The algorithms are prototypically implemented and evaluated based on artificial and real-world process execution logs. The results facilitate ISC design as well as validation and hence contribute to a digitalized ISC and compliance management.

A Week of Oral Terbinafine Pulse Regimen Every Three Months to Treat all Dermatophyte Onychomycosis.

Terbinafine has proved to treat numerous fungal infections, including onychomycosis, successfully. Due to its liver metabolization and dependency on the cytochrome P450 enzyme complex, undesirable drug interaction are highly probable. Additionally to drug interactions, the treatment is long, rising the chances of the appearance of side effects and abandonment. Pharmacokinetic data suggest that terbinafine maintains a fungicidal effect within the nail up to 30 weeks after its last administration, which has aroused the possibility of a pulse therapy to reduce the side effects while treating onychomycosis. This study’s goal was to evaluate the effectiveness of three different oral terbinafine regimens in treating onychomycosis due to dermatophytes. Sixty-three patients with onychomycosis were sorted by convenience in three different groups. Patients from group 1 received the conventional terbinafine dose (250 mg per day for 3 months). Group 2 received a monthly week-long pulse-therapy dose (500 mg per day for 7 days a month, for 4 months) and group 3 received a 500 mg/day dose for 7 days every 3 months, totaling four treatments. There were no statistical differences regarding the effectiveness or side effects between the groups. Conclusion: A quarterly terbinafine pulse regimen can be a possible alternative for treating onychomycosis caused by dermatophytes.