Potential use of psilocybin drugs in the treatment of depression.

INTRODUCTION: Depression is a common disabling psychiatric disorder, which - in extreme cases - may lead to suicide if untreated or inadequately treated. Despite the availability of various treatments for depression, including pharmacotherapy, there is still a need to search for new agents with higher effectiveness and faster onset of action, especially for patients with treatment-resistant depression. AREAS COVERED: A substance that has attracted considerable attention for nearly a decade is psilocybin, a natural psychedelic found in psilocybin mushrooms. In this study, we evaluated the efficacy and safety of psilocybin in the treatment of depression, based on pivotal randomized clinical trials. Moreover, we used findings from observational studies regarding recreational use. We also looked at ongoing clinical trials and discussed the registration status and clinical potential of the drug. EXPERT OPINION: Clinical phase I-II trials published to date reported promising results for psilocybin in the treatment of patients with major depressive disorder and treatment-resistant depression, in a relatively short time after administration. However, before psilocybin is approved for use and administered to patients with depression, the results of large ongoing phase III clinical trials are needed to confirm its efficacy and safety and to change the way it is perceived by physicians and patients.

Comparative safety of high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis.

OBJECTIVE: This study aimed to compare the safety profile of high-efficacy disease-modifying therapies (DMTs) natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, as well as a potentially high-efficacy DMT, ponesimod, in adult patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We included randomized controlled trials (RCTs) with at least 48-week follow-up investigating the use of natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, and ponesimod, as well as other DMTs, in adult patients with RRMS. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The Cochrane Collaboration tool to assess the risk of bias for RCTs was used. RESULTS: A total of 33 RCTs were included in the systematic review and NMA. A higher rate of adverse events (AEs) was revealed for alemtuzumab versus all other high-efficacy DMTs; for alemtuzumab (average probability of an event: 98.2%) versus placebo (86.2%); for cladribine (3.5 mg; 90.5%) versus ozanimod (1 mg; 84.2%) and placebo; as well as for ocrelizumab (95.5%) versus ozanimod, ofatumumab (88.9%), fingolimod (87.4%), natalizumab (82.8%), and placebo. No significant differences were found between drugs in terms of serious AEs except for cladribine (3.5 mg, 17.3%) versus ocrelizumab (10.3%) and ofatumumab (16.6%) versus ocrelizumab. Significant differences in AEs leading to the discontinuation of study drug were found only for ponesimod (10.1%) versus alemtuzumab (12 mg, 3.0%) and placebo (4.2%). No differences were found in terms of upper respiratory tract infections, nasopharyngitis, fatigue, and nausea between individual high-efficacy DMTs as well as between DMTs and placebo. The results of the NMA indicated a higher risk of infections for alemtuzumab (12 mg) versus ocrelizumab, for cladribine (3.5 mg) versus ofatumumab and placebo, and for ofatumumab versus placebo. For serious infections and urinary tract infections, a significant increase was found only for alemtuzumab (12 mg) versus ocrelizumab, while no differences were found between the other DMTs or between DMTs and placebo. Headache was more common for alemtuzumab (12 mg) as compared with all the other high-efficacy DMTs and placebo, as well as for cladribine versus natalizumab and fingolimod versus natalizumab. CONCLUSION: The commonly reported AEs are generally similar among high-efficacy DMTs. However, based on P scores for most analyzed endpoints, natalizumab and ocrelizumab were shown to be the safest DMTs. Considering the limitations of indirect comparisons, further research is needed to confirm our findings, preferably head-to-head RCTs and large observational studies.

Chest computed tomography versus RT-PCR in early diagnostics of COVID-19 - a systematic review with meta-analysis.

The purpose of this study was to compare the sensitivity and specificity of computed tomography (CT) scans of the chests of patients with the reference reverse-transcription real-time polymerase chain reaction (RT-PCR) in early diagnosis of COVID-19. A systematic review with meta-analysis for numerical outcomes was performed, including 10 studies (6528 patients). High risk of systematic bias (spectrum bias) was demonstrated in all studies, while in several studies research information bias was found to be possible. The sensitivity of CT examination ranged from 72% to 98%, and the specificity from 22% to 96%. The overall sensitivity of the CT scan was 91% and the specificity 87% (95% CI). Overall sensitivity of the RT-PCR reference test was lower (87%) than its specificity (99%) (95% CI). No clear conclusion could be drawn on the rationale of using CT scanning in the early diagnosis of COVID-19 in situations when specific clinical symptoms and epidemiological history would indicate coronavirus infection. The sensitivity of the CT test seems to be higher than that of the RT-PCR reference test, but this may be related to the mode of analysis and type of material analysed in genetic tests. CT scanning could be performed in symptomatic patients, with a defined time interval from symptom onset to performing CT or RT-PCR, and it should be explicitly included as an additional procedure when initial coronavirus genetic test results are negative, while clinical symptoms and epidemiological history indicate possible infection. However, a reference test showing the presence of coronavirus genetic material is essential throughout the diagnostic and treatment process.

Productivity Loss Among Parents of Children With Inflammatory Bowel Diseases in Relation to Disease Activity and Patient's Quality of Life.

OBJECTIVES: To assess the productivity losses among the parents of children with inflammatory bowel diseases (IBDs) in Poland and their relationship with disease activity and the patient's quality of life. METHODS: A questionnaire-based self-reported Internet survey was conducted among the parents of patients (0--17 years old) with a diagnosis of ulcerative colitis (UC) or Crohn disease (CD). Data on indirect and direct costs, general patient characteristics, disease activity, pharmacological treatment, and children's quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) were collected. RESULTS: A total of 113 completed questionnaires were obtained. Remission was reported in 58.6% of cases. Severe disease was more common in patients with UC (7.3% vs 2.9%). The mean reduction in parents' daily activities was 40% (range: 0%-100%). The mean (SD) reduction of parents' work productivity because of absenteeism was 21% (0.27), and the mean cost was &OV0556;902.77 (1136.90) per year per parent. The mean (SD) productivity loss at paid work of a working parent (presenteeism) was 35% (0.31) and the mean (SD) cost was &OV0556;1125.13 (1121.16) per year per parent. The PedsQL score was significantly higher among patients with inactive than with active disease. CONCLUSIONS: A significant difference between patients with inactive and active disease was observed for the total reduction of parent's work productivity and the PedsQL score. A negative correlation was observed for indirect costs and the PedsQL score for the whole study population; better health-related quality of life among patients in remission was revealed.

Coffee consumption and colorectal cancer risk: a dose-response meta-analysis on prospective cohort studies.

Evidence regarding the influence of coffee drinking on colorectal cancer (CRC) is limited, and it remains unclear whether coffee consumption is associated with the risk of the disease. To clarify this association, a comprehensive meta-analysis was performed. The risk of CRC was compared between the categories of coffee consumption, and a dose-response relationship was studied using restricted cubic splines. We did not find evidence for the association between coffee consumption and CRC risk. Among alternative study inclusions, when using pooled projects, coffee consumption was related with a decreased risk of colon cancer in a subgroup analysis of never-smokers and in Asian countries, and with an increased risk of rectal cancer in an analysis of the general population and after restriction to women, never-smokers, and European countries. In conclusion, the association between coffee consumption and CRC risk is controversial and should be clarified in further cohort studies.

Cost-utility analysis of 1-year treatment with adalimumab/standard care and standard care alone for ulcerative colitis in Poland.

PURPOSE: Until recently, surgery was the only remaining choice for moderate to severe chronic ulcerative colitis patients who failed standard treatment or when it was not tolerated. Anti-TNFα treatment is a new, non-invasive option for the management of ulcerative colitis. The objective of this study was to assess the cost-effectiveness of induction and maintenance treatment up to 1 year of ulcerative colitis with adalimumab/standard care and standard care alone in Poland. METHODS: A Markov model was used to estimate the expected costs and effects of adalimumab/standard care and a standard care alone. For each treatment option, the costs and quality adjusted life years were calculated to estimate the incremental cost-utility ratio. The analysis was performed from the perspective of the Polish public payer and society over a 30-year time horizon. Different direct and indirect costs and utility values were assigned to the various model health states. RESULTS: The treatment of ulcerative colitis patients with adalimumab/standard care up to 1 year instead of a standard care alone resulted in 0.14 additional years of life with full health (QALYs). The incremental cost-utility ratio of adalimumab/standard care compared to the standard care alone is estimated to be 76,120 €/QALY gained from NHF perspective and 71,457 €/QALY gained from social perspective. CONCLUSIONS: The biologic treatment of ulcerative colitis patients with adalimumab/standard care is more effective but also more costly compared with standard care alone.

Disease activity, quality of life and indirect costs of psoriatic arthritis in Poland.

The aim of the study was to assess the indirect costs, health-related quality of life and clinical characteristics of patients with psoriatic arthritis (PsA), measured using a PsA disease activity index in Poland. Additionally, we aimed to investigate the association between the activity, utility of PsA-affected patients and productivity loss in a Polish setting. A questionnaire survey was conducted to assess disease activity, as well as productivity loss, and a paper version of the EuroQoly-5D-3L questionnaire was used to assess productivity loss and the quality of life. Indirect costs were assessed with the human capital approach employing the gross domestic product (GDP) per capita, gross value added (GVA) and gross income (GI) per worker in 2014 in Poland and were expressed in Polish zlotys (PLN) as well as in euros. The correlation was presented using the Spearman correlation coefficient. Our analysis was performed on the basis of 50 full questionnaires collected. We observed a mean utility value of 0.6567. The mean number of days off work was 2.88 days per month, and mean on-the-job productivity loss was 24.1 %. Average monthly indirect costs per patient were €206.7 (864.01 PLN) calculated using the GDP; €484.56 (2025.46 PLN) calculated using the GVA; and €209.70 (876.56 PLN) calculated using the GI. PsA reduces the patients' quality of life as well as their productivity loss associated with both absenteeism and presenteeism. Total indirect costs were negatively correlated with utility. The greater the disease activity, the lower the utility and the greater the indirect costs.

Disease activity, quality of life and indirect costs of reduced productivity at work, generated by Polish patients with ankylosing spondylitis.

OBJECTIVES: The aim of the study was to investigate the association between activity of ankylosing spondylitis (AS) and decrease in quality of life as well as productivity loss of affected patients in a specified group of patients in the Polish setting. MATERIAL AND METHODS: An questionnaire survey was conducted using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) to assess disease activity, as well as the Work Productivity and Activity Impairment Questionnaires to assess productivity loss; quality of life was presented as utility calculated using the EuroQol 5 questionnaire and also measured on a visual analogue scale (VAS). Indirect costs were assessed with the human capital approach implying gross domestic product per capita or gross value added per worker in Poland in 2014 and were expressed in Polish zlotys (PLN) as well as in euros. Correlation was presented using Spearman's rank correlation coefficient. RESULTS: We performed our analysis based on 78 full questionnaires collected. A mean BASDAI score of 5.91 in the analysed group of patients was detected and mean utility of 0.5135 was observed. Average quality of life measured on the visual analogue scale was 46.55. Mean number of days off work was 45.26 days per year and mean on-the-job productivity loss was 49.29%. Average annual indirect costs per patient were €4241 (17 686 PLN) calculated using gross domestic product and €10 172 (42 417 PLN) estimated using gross value added. Total productivity loss was significantly correlated with disease activity (strong correlation of 0.6005) and utility (moderate correlation of -0.3698). CONCLUSIONS: Ankylosing spondylitis causes a great decrease in quality of life as well as patients' productivity loss associated with both absenteeism and presenteeism. The greater the disease activity is, the lower is the utility, the lower is the quality of life measured on the VAS, and the greater are the total annual indirect costs. Total indirect costs were negatively correlated with utility; although the association was moderate, it was significant.

The safety of dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter 2 (SGLT-2) inhibitors added to metformin background therapy in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

The aim of the present meta-analysis was to assess the safety profile of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors in comparison with placebo as add-on to metformin therapy in patients with type 2 diabetes. Randomized controlled trials and controlled clinical trials were identified by searching Pubmed, Embase and the Cochrane Central Register of Controlled Trials database until 15 July 2013. All included studies were critically appraised and analysed with the use of Review Manager 5.1.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement protocol. Twenty randomized and double-blinded studies published in 22 articles fulfilled the inclusion criteria for meta-analysis. The overall results demonstrated that the use of oral antidiabetic agents (analysed separately and together) was not associated with any significantly increased risk of any serious adverse events including hypoglycaemia and gastrointestinal disorders. Moreover, the use of DPP-4 or SGLT-2 inhibitors significantly decreased risk of diarrhoea compared with placebo, when given concomitantly with metformin. However, we found that the SGLT-2 inhibitors were more likely to cause a genital infection. Despite some limitations, the findings of this meta-analysis indicate that DPP-4 or SGLT-2 inhibitors have favourable safety profile, and such therapy, when combined with metformin is well tolerated.

Systematic review of the effectiveness of biological therapy for active moderate to severe ulcerative colitis.

BACKGROUND AND AIM: The aim of this systematic review was to evaluate the efficacy and safety of biological agents (vedolizumab, abatacept, visilizumab, golimumab) in patients with active moderate to severe ulcerative colitis. METHODS: This paper was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The systematic literature search was performed in PubMed, Embase, Cochrane Library, and other databases until December 27, 2013 to identify randomized controlled trials fulfilling the established inclusion criteria for this review. RESULTS: Eight randomized controlled trials were included in the systematic review. Vedolizumab was significantly more effective compared with placebo (P < 0.05) increasing the percentage of patients with a clinical response, clinical remission and mucosal healing in the induction phase, and patients with a clinical remission and mucosal healing in the maintenance phase. Similarly, golimumab was significantly more effective than placebo (P < 0.05) regarding the percentage of patients with a clinical response and mucosal healing in the induction phase, and patients with a clinical response, clinical remission, and mucosal healing in the maintenance phase. The safety of these two biological agents was comparable with placebo during the treatment (P > 0.05). However, the efficacy of visilizumab or abatacept was related to the higher risk of treatment failure and a worse safety profile than placebo. CONCLUSIONS: The results of the systematic review demonstrated that the efficacy and safety of particular biological agents are differentiated. Vedolizumab and golimumab occurred more effective, and comparably as safe as placebo in patients with active moderate to severe ulcerative colitis increasing the number of available therapeutic options.

The effectiveness of dimethyl fumarate monotherapy in the treatment of relapsing-remitting multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: Dimethyl fumarate (BG-12, Tecfidera®) is a new oral drug approved by FDA and EMA in March 2013 for relapsing - remitting multiple sclerosis (RRMS). The drug was much anticipated because of its possible superiority over currently available medications: fingolimod and teriflunomide as the only MS treatments currently available in oral form. OBJECTIVE: The aim of this systematic review with meta-analysis was to assess the efficacy and safety of BG-12 in the treatment of RRMS. METHODS: A systematic literature search was conducted in Medline/PubMed, EMBASE, and Cochrane Library up till 3(rd) November, 2013. We sought all published randomized clinical trials evaluating the use of dimethyl fumarate for the treatment of patients with RRMS. All included studies were critically appraised and analyzed with the use of Review Manager 5.1.0. software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. RESULTS: Two trials, DEFINE and CONFIRM involved 2 651 patients and compared dimethyl fumarate taken either two or three times daily with placebo in patients with RRMS. Additionally in CONFIRM trial third group of patients received glatiramer acetate. The overall results of the meta-analysis showed that BG-12 (at both dosages) given to patients with RRMS is safe and statistically significantly more effective than placebo in reducing the proportion of patients who had a relapse by 2 years, the rate of disability progression and the mean number of gadolinium-enhancing lesions at 2 years. The comparison between BG-12 and glatiramer acetate revealed that the analyzed agent could potentially be more effective in the treatment of RRMS. CONCLUSIONS: Despite limited RCTs data available, both analyzed BG-12 regimens showed their efficacy on clinical disease parameters and other measures of disease activity in RRMS. The safety profile of the study agent was acceptable.

Safety Profile of First-Line Targeted Therapies in Elderly and/or Comorbid Chronic Lymphocytic Leukaemia Patients (Unfit Subpopulation). A Systematic Review and Network Meta-Analysis.

This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1-5), followed by venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1-5. The use of Bruton's tyrosine kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities.

Provision of special diets to children in public nurseries and kindergartens in Kraków (Poland).

Background: A specialized diet could be due to an allergy or other medical needs and also religious or cultural reasons. This study aimed to assess the availability and provision of special diets in kindergartens and nurseries financed by the Municipality of Kraków. Methods: This observational cross-sectional study was based on a diagnostic survey carried out using the Computer-Assisted Web Interview method and addressed to the managers of nurseries (n = 21) and kindergartens (n = 71) and, separately, to the parents of children attending these facilities (n = 1,096). Non-parametric tests were applied for an unadjusted comparison between children at nurseries and those at kindergartens. Results: Children with particular dietary requirements received special diet meals in 95.2% of nurseries and 60.5% of kindergartens. The availability of special diets was associated with the type of facility (p = 0.001), the number of children who ate in the facility (p = 0.032), and the daily cost of meals served to children (p = 0.009). The cost of meals was higher in kindergartens that offered special diets vs. those that did not offer such diets (p < 0.001). According to parents, 96.4% of the total number of children ate meals served in the facilities. In nurseries, 16.1% of children were on a special diet (as per the doctor's recommendations in 11.7% of cases and according to parents' own choice in 4.4%). In kindergartens, a special diet was served to 12.7% of children (doctor's recommendations, 8.5%; parents' own choice, 4.2%). The most common reason for using a special diet was food allergy (8.2% of children in nurseries and 5.8% of children in kindergartens). It was reported more often by the parents of children attending nurseries than by the parents of children attending kindergartens (8.0% vs. 4.2%, p = 0.007). The requirement for a special diet was found to be associated with the age of children (p < 0.033) and the use of oral treatment for chronic disease (p < 0.001). Conclusion: Providing special diets for children is better in nurseries than in kindergartens. Legal regulations are urgently needed to ensure equal access to adequate nutrition for all children with special dietary needs in childcare facilities.

Evidence for external beam radiotherapy in mediastinal Hodgkin and non-Hodgkin lymphoma - systematic review.

INTRODUCTION AND OBJECTIVE: Proton beam therapy (PBT) provides the opportunity for a more localized delivery of high energy protons and may reduce the damage to healthy tissues and vital organs. The aim of this review was to assess the effects of proton therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma treated with mediastinal irradiation. REVIEW METHODS: A systematic search of EMBASE, MEDLINE via OVID and Cochrane Library was conducted in May 2022 according to PRISMA guidelines to identify relevant data on the efficacy and toxicity of proton beam therapy for patients diagnosed with Hodgkin or non-Hodgkin lymphoma. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: Of 566 screened abstracts (430 after de-duplication) 11 studies with a total of 529 patients were included. All studies were case series published between 2011-2021. Median range of follow-up time was 15-63.6 months. The overall survival (OS) for 2 years varied from 91% - 98% for 5 of the included studies. Three of the included studies had favourable outcomes with 2-year progression-free survival (PFS) ranging from 73% - 94%. Skin reaction, oesophagitis and fatigue were found to be the most common grade 1 and grade 2 toxicities. No acute or late grade 4 and higher toxicities/adverse events were observed. SUMMARY: There are data indicating that PBT may to be an effective treatment against mediastinal Hodgkin and non-Hodgkin lymphoma. Because all the studies were case series, the authors of this review have little confidence in the evidence. There remains a need for well-designed randomized controlled trials to inform about the optimal approach to proton irradiation in HL and NHL.

Clinical aspects of reimbursement policies for orphan drugs in Central and Eastern European countries.

Objectives: The aim of this study was to characterize the reimbursement policy for orphan drugs (ODs) in Central and Eastern European (CEE) countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedure, selected economic indicators, and the drug type according to indications. Materials and methods: A list of authorized medicines with orphan designation and information about active substance, Anatomical Therapeutic Chemical (ATC) classification, and therapeutic area was extracted from the web-based register of the European Medicines Agency (EMA). A country-based questionnaire survey was performed between September 2021 and January 2022 in a group of selected experts from nine CEE countries (an invitation was sent to 11 countries). A descriptive and statistical analysis was conducted to determine statistical significance, correlations, between the drug or country characteristic and the positive recommendation or reimbursement of ODs. Results: The proportion of reimbursed orphan drugs differed between countries, ranging from 17.7% in Estonia to 49.6% in Hungary (p < 0.001). The odds that ODs were reimbursed were reduced in countries with a "strong" level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), the presence of other additional specific clinical aspects (e.g., genomic data) considered in the reimbursement decision (p < 0.001) and mandatory (without exception) safety assessments (p=0.004). The probability that ODs were reimbursed was increased in countries with a "moderate" level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), when reimbursement decisions are dependent on the EMA registration status and orphan drug designation (p < 0.001), the presence of the "positive HTA recommendation guarantees reimbursement" policy (p < 0.001), higher GDP per inhabitant (p=0.003), and higher healthcare expenditure (p < 0.001). Conclusion: We found that there are differences among CEE countries in the reimbursement of orphan drugs, and we identified aspects that may influence these differences. Safety, efficacy, and specific clinical aspect issues significantly influenced reimbursement decisions. Antineoplastic and immunomodulating agents drugs were the largest group of ODs and increased the chance of getting a positive recommendation. The higher GDP per inhabitant and healthcare expenditures per inhabitant were positively linked to the chance that an OD receives reimbursement.

[Clinical efficacy and safety of prolonged use of the valganciclovir for the treatment of cytomegalovirus disease in patients after kidney transplantation]. / Skutecznosc kliniczna oraz bezpieczenstwo przedluzonego stosowania walgancyklowiru w leczeniu choroby cytomegalowirusowej u chorych po przeszczepie nerki.

UNLABELLED: Cytomegalovirus infection is particularly dangerous for patients undergoing solid organs transplantation. Among these patients cytomegalovirus disease (CMV) may occur. CMV disease is associated with increased mortality, organ damage and reduced graft survival. THE AIM OF THE STUDY was to determine the clinical outcomes (clinical efficacy and safety profile) for the use of valganciclovir administered for 200 days compared to standard period of 100 days in the prevention of cytomegalovirus disease in seronegative patients after kidney transplantation from infected donor (high risk patients). MATERIAL AND METHODS: A systematic review of literature published during the period: 1st January 1966-31st October 2010, was performed in order to assess the efficacy and safety of valganciclovir in the treatment of cytomegalovirus disease. Databases MEDLINE (PubMed), EMBASE and Cochrane were searched. RESULTS: A systematic review yielded 1 randomized and 3 nonrandomized clinical trials. 200 days prophylaxis with valganciclovir significantly decreased a risk of: cytomegalovirus disease, CMV viral load, opportunistic infections; percentage of patients with high viral load was also significantly decreased compared to 100 days therapy. The safety profile of extended therapy was similar to that observed within 100 days prophylaxis. The higher risk of leucopenia in the 200 days than 100 days group was the only one adverse event that met statistical significance. The results of non-randomized trials were comparable to those mentioned above. CONCLUSION: Prolonged prophylaxis of cytomegalovirus till 200 days in high-risk patients (D+/B-) is safe and provides significant therapeutic benefits.

[The evaluation of cost-effectiveness and cost-utility of valganciclovir for the prophylaxis of cytomegalovirus disease to 200 days after kidney transplantation]. / Ocena kosztowej efektywnosci i kosztowej uzytecznosci stosowania walgancyklowiru w profilaktyce wystapienia choroby cytomegalowirusowej do 200. dnia od przeszczepu nerki.

UNLABELLED: Standard procedure for cytomegalovirus disease (CMV) prophylaxis in kidney transplant patients was the administration of valganciclovir for up to 110 days after organ transplant. This prophylaxis has been extended up to 200 days in Poland since 2011. The decision was based on the results of clinical trials which showed significant clinical benefit in case of prolonged administration of the drug. The aim of the analysis was to provide the economic evaluation of extending the CMV prophylaxis with co-financed from public funds Valcyte (valganciclovirum; 60 tab. a 450 mg; Roche Polska Sp. z o.o.) from 110 to 200 days, in the high risk patients group after kidney transplant (seronegative recipient and infected donor, D+/R-). The analysis was performed from the Polish healthcare payer's perspective. MATERIAL AND METHODS: All methods used in the following study were consistent with the Requirements of the Polish HTA Agency (AHTAPOL). The cost-effectiveness and the cost-utility analysis were performed on the basis of a randomised study which was identified as a result of the systematic search of the medical databases, comparing 200 days valgancyclovir administration with 100 days drug use as a prophylaxis of CMV disease in the patients group mentioned above. The Markov model was developed, simulating the disease evolution over time considering a high risk patient after kidney transplant treated with valgancicloviras the CMV disease prophylaxis. The disease period was divided into health states that are the most probable for this condition and the transitions probabilities between them were identified and assigned. Based on the clinical trial results, registry database of health conditions usability and experts' opinion, all health states (i.e. death, kidney transplant, CMV disease) were attributed with utilities and costs. The direct costs, important from the Polish healthcare payer's perspective, were included in the analysis. Extension of the proposed model in the series of one month time cycles made it possible to assess long-term (assumed time horizon was median patient's life expectancy--23,5 years) costs and clinical effects of the compared technologies. RESULTS: The Incremental Cost-Effectiveness Ratio (ICER) was 39 669 008 PLN and The Incremental Cost-Utility Ratio (ICUR) was 48 008 PLN in the specified time horizon. The result is well below the accepted threshold of profitability in Poland (assuming tripled GDP per capita cost-utility threshold, i.e. 99 543 PLN), which means that the therapy is cost-effective. CONCLUSIONS: The results of the analysis confirmed that the 200 days use of valganciclovirin the prevention of CMV disease compared to standard 110 days therapy is economically justified from the Polish healthcare payer's perspective.

[Administration of conestat alfa, human C1 esterase inhibitor and icatibant in the treatment of acute angioedema attacks in adults with hereditary angioedema due to C1 esterase inhibitor deficiency. Treatment comparison based on systematic review results]. / Konestat alfa, ludzki inhibitor C1 esterazy oraz ikatybant w leczeniu ostrych ataków obrzeku u osób doroslych z dziedzicznym obrzekiem naczynioruchowym spowodowanym niedoborem inhibitora C1 esterazy. Porównanie opcji terapeutycznych na podstawie przegladu systematycznego.

INTRODUCTION: Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH), and icatibant in the treatment of acute angioedema attacks in adults with HAE. MATERIALS AND METHODS: A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH, and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE, and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate OR synonyms OR icatibant). Only randomized clinical studies were selected. RESULTS: Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH, and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo. CONCLUSIONS: Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.

Cost-utility analysis of Ruconest(®) (conestat alfa) compared to Berinert(®) P (human C1 esterase inhibitor) in the treatment of acute, life-threatening angioedema attacks in patients with hereditary angioedema.

INTRODUCTION: Administration of human C1 esterase inhibitor (Berinert(®) P) from target import is the most widespread treatment strategy for patients with hereditary angioedema (HAE). However, a therapeutic health program including Ruconest(®) (conestat alfa) could shorten a patient's expectancy for a life-saving treatment. AIM: To evaluate the cost-utility of Ruconest(®) (conestat alfa) financed from public funds within the newly introduced therapeutic health program compared with Berinert(®) P (human C1 esterase inhibitor) in the treatment of acute angioedema attacks in adults with HAE. MATERIAL AND METHODS: The cost-utility analysis from the Polish healthcare payer's perspective was performed for 1 year (2012). The costs and health outcomes were simulated for three pairs of eligible HAE patient groups (active treatment and corresponding placebo). The incremental costs of each intervention compared with placebo were listed together (direct or indirect comparisons between options were impossible due to limited clinical data available). RESULTS: The incremental cost-utility ratios (ICURs) for the evaluated interventions compared with placebo were as follows: EUR 15,226 per QALY (Ruconest(®)) and EUR 27,786 per QALY (Berinert(®) P). The probability of cost-utility (ICUR < EUR 24,279 per QALY) assessed for Ruconest(®) administered in the case of acute angioedema attack was 61% and 41% for Berinert(®) P. CONCLUSIONS: The administration of Ruconest(®) in acute life-threatening angioedema attacks is economically justified from the Polish healthcare payer's perspective, results in lower costs and is characterized by higher cost-utility probability compared with Berinert(®) P.

Comparative safety of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma: a systematic review and network meta-analysis.

Objective: This study aimed to compare the safety profile of tyrosine kinase inhibitors (TKIs) approved for use as monotherapy or combination therapy for the first-line treatment of adult patients with metastatic clear cell renal cell carcinoma (RCC). Methods: A systematic review with frequentist network meta-analysis (NMA) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included randomized controlled trials (RCTs) investigating the use of: cabozantinib, pazopanib, sorafenib, sunitinib, tivozanib, cabozantinib + nivolumab, lenvatinib + pembrolizumab, axitinib + avelumab, and axitinib + pembrolizumab in previously untreated adult patients with metastatic clear cell RCC. Eligible studies were identified by two reviewers in MEDLINE (via PubMed), EMBASE, and Cochrane Library. The risk of bias for RCTs was assessed using the Cochrane Collaboration tool. The P score was used to determine the treatment ranking. The mean probability of an event along with the relative measures of the NMA was considered with the treatment rankings. Results: A total of 13 RCTs were included in the systematic review and NMA. Sorafenib and tivozanib used as monotherapy were the best treatment options. Sorafenib achieved the highest P score for treatment discontinuation due to adverse events (AEs), fatigue, nausea, vomiting of any grade, and hypertension of any grade or grade ≥3. Tivozanib achieved the highest P score for AEs, grade ≥3 AEs, dose modifications due to AEs, and grade ≥3 diarrhea. Sunitinib was the best treatment option in terms of diarrhea and dysphonia of any grade, while cabozantinib, pazopanib, and axitinib + pembrolizumab-in terms of grade ≥3 fatigue, nausea, and vomiting. TKIs used in combination were shown to have a poorer safety profile than those used as monotherapy. Lenvatinib + pembrolizumab was considered the worst option in terms of any AEs, grade ≥3 AEs, treatment discontinuation due to AEs, dose modifications due to AEs, fatigue of any grade, nausea, vomiting, and grade ≥3 nausea. Axitinib + avelumab was the worst treatment option in terms of dysphonia, grade ≥3 diarrhea, and hypertension, while cabozantinib + nivolumab was the worst option in terms of grade ≥3 vomiting. Interestingly, among the other safety endpoints, cabozantinib monotherapy had the lowest P score for diarrhea and hypertension of any grade. Conclusion: The general safety profile, including common AEs, is better when TKIs are used as monotherapy vs. in combination with immunological agents. To confirm these findings, further research is needed, including large RCTs.