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.

In vitro cytotoxic activity evaluation of phenytoin derivatives against human leukemia cells.

Hydantoin derivatives, including phenytoin (5,5-diphenylhydantoin), have recently gained attention as they possess a variety of important biochemical and pharmacological properties. Nevertheless, available information on anticancer activity of hydantoin derivatives is still scarce. Here, we evaluated possible antileukemic potential of four phenytoin analogs, namely: methyl 2-(2,4-dioxo-5,5-diphenylimidazolidin-3-yl)propanoate (1), methyl 2-(1-(3-bromopropyl)-2,4-dioxo-5,5-diphenylimidazolidin-3-yl)propanoate (2), 1-(3-bromopropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (3) and 1-(3-bromobutyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (4). The experiments were performed on human acute histiocytic lymphoma U937 cells and human promyelocytic leukemia HL-60 cells. The present study was conducted using spectrophotometric 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay and the electronic Beckman-Coulter method. We observed temporary changes in the leukemia cell viability, volume and count. The effects of the four 5,5-diphenylhydantoin derivatives on U937 and HL-60 cells depended on the agent tested and its concentration, the time intervals after the compound application, and the leukemia cell line used. HL-60 cells were more sensitive than U937 cells to the action of the phenytoin analogs (1-4). The antileukemic activities of the three bromoalkyl diphenylhydantoin derivatives (2, 3, and 4) were stronger than that of the compound 1 [methyl 2-(2,4-dioxo-5,5-diphenylimidazolidin-3-yl) propanoate], with no bromoalkyl substituent. The structural modifications of 5,5-diphenylhydantoin are responsible for such varied antileukemic potential of its four derivatives.

Efficacy and safety of mirikizumab compared with currently approved biologic drugs for the treatment of ulcerative colitis: A systematic review and network meta-analysis.

Ulcerative colitis (UC) is a serious health problem that requires a constant need to identify new effective drugs. The aim of this study was to assess the efficacy and safety of mirikizumab compared with other biologic drugs approved for the treatment of moderately to severely active UC. This systematic review with frequentist network meta-analysis (NMA) included randomized controlled trials (RCTs) that evaluated the use of adalimumab, golimumab, infliximab, mirikizumab, vedolizumab, and ustekinumab compared with placebo or with another approved biologic drug. The NMA was conducted using the netmeta R software package. The P score was used to determine the treatment ranking. A total of 14 RCTs were included in the analysis. No significant differences were observed in the incidence of clinical response and remission between mirikizumab and other drugs. Mirikizumab was superior to placebo for clinical response (induction: odds ratio [OR] = 2.38; 95% confidence interval [CI]: 1.63-3.48; maintenance: OR = 3.31, 95% CI: 1.59-6.89) and remission (induction: OR = 2.09, 95% CI: 1.20-3.63; maintenance: OR = 2.96; 95% CI: 1.62-5.40). The probability plot indicated that infliximab might be the most effective option in terms of both clinical response and remission (P score, 0.8971 and 0.8814, respectively) in induction phase. No significant differences were noted between the studied drugs in any adverse events (AEs), serious AEs (SAEs) and infections for the induction phase, and in any AEs, infections and serious infections for the maintenance phase. The drugs differed in terms of discontinuation due to AEs (induction and maintenance phases) as well as SAEs and serious infections (maintenance phase). Mirikizumab did not differ from other biologics in terms of clinical response and remission for both induction and maintenance phases in patients with UC. Mirikizumab during the induction phases achieved rank 3 for clinical response and rank 5 for clinical remission. Therefore, it represents a valuable treatment option. The lack of significant differences in the risk of AEs and SAEs suggests that mirikizumab has a similar safety profile to the other drugs.

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.

The Potential of Scopolamine as an Antidepressant in Major Depressive Disorder: A Systematic Review of Randomized Controlled Trials.

Major depressive disorder is one of the most severe mental disorders. It strongly impairs daily functioning, and, in extreme cases, it can lead to suicide. Although different treatment options are available for patients with depression, there is an ongoing search for novel therapeutic agents, such as scopolamine (also known as hyoscine), that would offer higher efficacy, a more rapid onset of action, and a more favorable safety profile. The aim of our study was to review the current clinical evidence regarding the use of scopolamine, a promising therapeutic option in the treatment of depression. A systematic literature search was performed using PubMed, Embase, and CENTRAL databases up to 5 June 2023. We included randomized placebo-controlled or head-to-head clinical trials that compared the clinical efficacy and safety of scopolamine in the treatment of major depressive disorder. Two reviewers independently conducted the search and study selection and rated the risk of bias for each study. Four randomized controlled trials were identified in the systematic review. The included studies investigated the use of scopolamine administered as an oral, intramuscular, or intravenous drug, alone or in combination with other antidepressants. The results indicated that scopolamine exerts antidepressant effects of varying intensity. We show that not all studies confirmed a statistically and clinically significant reduction of depressive symptoms vs. placebo. A broader perspective on scopolamine use in antidepressant treatment should be confirmed in subsequent large randomized controlled trials assessing both effectiveness and safety. Therefore, studies directly comparing the effectiveness of scopolamine depending on the route of administration are required.

Opicapone as an add-on to levodopa for reducing end-of-dose motor fluctuations in Parkinson's disease: a systematic review and meta-analysis.

Aim: To assess the clinical efficacy and safety profile of opicapone (25 and 50 mg once daily) versus placebo. Patients: Levodopa-treated adults with Parkinson's disease. Material & methods: A systematic review and meta-analysis were conducted. Results: Opicapone provided a greater reduction in the absolute OFF-time, increased the chances of ≥1-h reduction in the OFF-time and ≥1-h increase in the ON-time compared with placebo. Receiving opicapone more often facilitated levodopa dose reduction versus placebo. There were no differences in the occurrence of adverse events (severe and leading to drug discontinuation), but receiving opicapone increased the frequency of dyskinesia. Conclusion: Opicapone demonstrated superior clinical efficacy to placebo, with a comparable general safety profile.

New alternative in the treatment of rheumatoid arthritis: clinical utility of baricitinib.

Baricitinib is an innovative small-molecule drug that reversibly inhibits continuous activation of JAK/STAT pathway, thus reducing joint inflammation. The drug was approved for use as monotherapy or in combination with methotrexate (MTX) in the treatment of adults with moderately to severely active rheumatoid arthritis (RA). The aim of this paper was to review the studies on pharmacology, mode of action, pharmacokinetics, efficacy, and safety of baricitinib in patients with RA. Baricitinib provides an innovative approach to modulating the immune and inflammatory response in patients with RA, which is especially important in individuals who do not respond to disease-modifying antirheumatic drugs or standard biologic drugs (tumor necrosis factor inhibitors) or who lose response over time. Baricitinib therapy reduces symptoms of RA and improves the quality of life. Moreover, it has shown high efficacy and an acceptable safety profile in Phase III randomized controlled trials (RCTs) and become another JAK inhibitor approved for RA treatment, providing a useful alternative option. RCTs have revealed a significant benefit of baricitinib over placebo, MTX, and adalimumab in terms of standard efficacy outcomes, especially the American College of Rheumatology ACR20, ACR50, and ACR70 response rates. Additionally, a clinically meaningful improvement in patient-reported outcomes, including the quality of life, compared with placebo has been reported. The safety profile seems acceptable, although some rare but potentially severe adverse events have been observed, such as serious infections, opportunistic infections (eg, herpes zoster), malignancies, and cardiac or hepatic disorders. Baricitinib administered at an approved dose of 2 or 4 mg once daily offers a novel and promising alternative to parenterally administered biologic drugs used in RA treatment.

European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib.

Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time. The aim of this article was to review studies on the pharmacology, mode of action, pharmacokinetics, efficacy, and safety of tofacitinib in patients with RA. Tofacitinib has been shown to reduce symptoms of RA and improve the quality of life in the analyzed groups of patients. Moreover, it showed high efficacy and an acceptable safety profile in Phase III randomized clinical trials on RA and was the first JAK inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the RA therapy, thus providing a useful alternative treatment strategy. Randomized controlled studies revealed a significant benefit over placebo in efficacy outcomes (American College of Rheumatology [ACR] 20 and ACR50 response rates); accordingly, clinically meaningful improvements in patient-related outcomes compared with placebo have been reported. The safety profile seems acceptable, although some severe adverse effects have been observed, including serious infections, opportunistic infections (including tuberculosis and herpes zoster), malignancies, and cardiovascular events, which require strict monitoring irrespective of the duration of tofacitinib administration. As an oral drug, tofacitinib offers an alternative to subcutaneous or intravenous biologic drugs and should be recognized as a more convenient way of drug administration.

Comparison of In Vitro Antileukemic Activity of 4-Hydroperoxyifosfamide and 4-Hydroperoxycyclophosphamide.

BACKGROUND/AIM: The oxazaphosphorines, ifosfamide and cyclophosphamide, represent a class of alkylating agents. The aim of the present in vitro study was to compare antileukemic activity of 4-hydroperoxyifosfamide (4-OOH-IF) and 4-hydroperoxycyclophosphamide (4-OOH-CP). MATERIALS AND METHODS: The experiments were performed on MOLT-4 and ML-1 cells. The research was conducted using flow cytometry fluorescein diacetate/propidium iodide (PI), fluorescein-conjugated annexin V/PI, CaspGLOW Red Active Caspase-8 and -9, CellEvent™ Caspase-3/7 Green assays, and tetramethylrhodamine ethyl ester test. RESULTS: 4-OOH-IF and 4-OOH-CP distinctly reduced cell viability and triggered apoptosis and necrosis, causing changes in intracellular esterase activity, plasma membrane structure and integrity, caspase activation, and mitochondrial membrane potential. The oxazaphosphorines were responsible for the different antileukemic activities. 4-Hydroperoxyifosfamide appeared to be less cytotoxic against the leukemia cells than 4-hydroperoxycyclophosphamide. MOLT-4 cells were more sensitive to the action of the oxazaphosphorines than ML-1 cells. CONCLUSION: The findings provide a new insight on the mechanisms of cytotoxic action of 4-OOH-IF and 4-OOH-CP on the human acute lymphoblastic and myeloblastic leukemia cells.

In Vitro Antileukemic Activity of Formamidine Epidoxorubicin Analogs.

BACKGROUND/AIM: Epidoxorubicin is an anthracycline agent. The present study was undertaken to compare the antileukemic potential of epidoxorubicin and its two formamidine analogs containing either a morpholine moiety (EPIFmor) or a hexamethyleneimine moiety (EPIFhex) in the amidine group. MATERIALS AND METHODS: The experiments were performed in vitro on MOLT-4 cells using spectrophotometry, Coulter electrical impedance, flow cytometry, and light microscopy methods. RESULTS: The leukemia cell responses to the action of the anthracyclines were manifested in their different viability, count and volume, degree of apoptosis and necrosis, activity of caspases -8, -9, and -3/7, mitochondrial membrane potential, and in the cell-cycle distribution. In general, epidoxorubicin appeared to be the most active, and EPIFmor was more active than EPIFhex against MOLT-4 cells. CONCLUSION: The structural modifications of epidoxorubicin in the amidine group were responsible for the varied action of its formamidine analogs on human acute lymphoblastic leukemia cells.

In Vitro Effects of Bromoalkyl Phenytoin Derivatives on Regulated Death, Cell Cycle and Ultrastructure of Leukemia Cells.

BACKGROUND/AIM: To search for new antileukemic agents, the chemical structure of phenytoin was modified. A possible cytotoxic activity of three bromoalkyl phenytoin analogs, methyl 2-(1-(3-bromopropyl)-2,4-dioxo-5,5-diphenylimidazolidin-3-yl) propanoate (PH2), 1-(3-bromopropyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (PH3) and 1-(4-bromobutyl)-3-methyl-5,5-diphenylimidazolidine-2,4-dione (PH4) on regulated cell death, the cell cycle and cell ultrastructure was assessed. MATERIALS AND METHODS: The experiments were performed in vitro on HL-60 and U937 cells, using flow cytometry and electron microscopy methods. RESULTS: Application of PH2, PH3, and PH4 resulted in cell surface exposure of phosphatidylserine and plasma membrane impairment, caspase-8, -9, and -3/7 activation, dissipation of mitochondrial membrane potential, DNA breakage, cell-cycle disturbance and cell ultrastructural changes. In general, PH3 appeared to be the most active against the leukemia cells, and all bromoalkyl hydantoins, PH2-PH4, were more active in HL-60 cells than in U937 cells. CONCLUSION: The antileukemic activity of the bromoalkyl phenytoin analogs depended on the combination of N-hydantoin substituents and the human cell line used.