Current Pharmaceutical Design - Volume 28, Issue 24, 2022

Trabectedin, a tetrahydroisoquinoline alkaloid, is the first marine antineoplastic agent approved with special anticancer mechanisms involving DNA binding, DNA repair pathways, transcription regulation and regulation of the tumor microenvironment. It has favorable clinical applications, especially for the treatment of patients with advanced soft tissue sarcoma, who failed in anthracyclines and ifosfamide therapy or could not receive these agents. Currently, trabectedin monotherapy regimen and regimens of combined therapy with other agents are both widely used for the treatment of malignancies, including soft tissue sarcomas, ovarian cancer, breast cancer, and non-small-cell lung cancer. In this review, we have summarized the basic information and some updated knowledge on trabectedin, including its molecular structure, metabolism in various cancers, pharmaceutical mechanisms, clinical applications, drug combination, and adverse reactions, along with prospects of its possibly more optimal use in cancer treatment.

In our knowledge, using appropriate carriers in the delivery of chemotherapeutic drugs, would result in better targeting and therefore it would increase the effectiveness and decrease the side effects of drugs. Chitosan, a natural polymer derived from chitin, has attracted the attention of pharmaceutical industries recently. New research works show that chitosan can not only be used in drug delivery but it can also have some usages in the prevention and diagnosis of cancer. This means that using chitosan Nanoformulations can be a promising approach for prevention, diagnosis, and specially treatment of cervical cancer, the fourth common cancer among the women of the world. We aim to investigate the related papers to find a novel method and preventing more women from suffering.

Background: Although fluoxetine and, in the USA, escitalopram are approved for depression in adolescence, substantial concern surrounds antidepressant use in youth. Major controversies regarding the efficacy and safety (increased suicidality) of antidepressants exist. Introduction: The category of depression is very broad and overinclusive in terms of etiology, the role of psychosocial adversities severity, episodicity, presentation, and relationship with bipolarity. This heterogeneity, not fully considered in Randomized Controlled Trials (RCTs), may account for the disappointing results with respect to both the efficacy and safety. Methods: Based on the available literature, we will address the following topics: a) controversies regarding the definition of depression as a unique homogeneous condition with a unique type of pharmacological treatment; b) controversies about the interpretation of data from Randomized Controlled Trials (RCTs) on the efficacy of pharmacological treatments in adolescent depression; c) the interpretation of data regarding the safety of antidepressant treatment in adolescent depression, particularly in terms of increased suicidal risk. Results: According to RCTs, antidepressants are minimally to moderately more effective than placebo, principally based on very high placebo responses, and only fluoxetine shows more evidence of efficacy. These differences in meta-analyses are sometimes statistically but not clinically significant. Depression is a heterogeneous condition in terms of etiology, the role of psychosocial adversities severity, episodicity, presentation, and relationship with bipolarity. This heterogeneity may partly explain the low drug-placebo difference and the high placebo response (possibly related to a high level of natural recovery of adolescent depression). In the National Institute of Mental Health (NIMH)-funded studies, including a lower number of study sites and more reliable enrollment procedures, lower placebo response rates and greater group differences between medication and placebo were found. Robust evidence supports an increased risk of emergent suicidality after starting antidepressants. A clear age effect on suicidal risk after antidepressants is supported by a comprehensive meta-analysis, showing that suicidal risk increases with decreasing age, being markedly greater in subjects aged between 18 and 25 years. However, the term suicidality is too broad, as it includes suicidal ideation, suicidal attempts, and completed suicide, with a wide range of severity and pervasiveness. If emergent suicidality should be actively and carefully explored, empirical evidence, albeit weak, suggests that combined pharmacotherapy (antidepressant and/or lithium) associated with psychotherapy may be helpful in reducing pretreatment suicidal ideation and suicidal risk. Conclusion: Moderate to severe depression should be treated with psychotherapy and/or fluoxetine, the bestsupported medication, and treatment-resistant adolescents should always receive combined treatment with psychotherapy. Suicidal ideation, particularly with a plan, should be actively explored before starting an antidepressant, as a reason for the closest monitoring. Emergent suicidality after starting antidepressants, as well as antidepressant-related activation, should also be closely monitored and may lead to antidepressant discontinuation. Although no response to pharmacotherapy and psychotherapy may occur in up to 40% of depressed adolescents, possible predictors or mediators of poorer response in adolescents are uncertain, and only a few studies support possible treatment strategies. Finally, studies exploring the efficacy of antidepressants in specific depression subtypes, i.e., based on prevalent psychopathological dimensions (apathy, withdrawal, impulsivity), are warranted.

The mean global lifetime risk of neurological disorders such as stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD) has shown a large effect on economy and society. Researchers are still struggling to find effective drugs to treat neurological disorders and drug delivery through the blood-brain barrier (BBB) is a major challenge to be overcome. The BBB is a specialized multicellular barrier between peripheral blood circulation and neural tissue. Unique and selective features of the BBB allow it to tightly control brain homeostasis as well as the movement of ions and molecules. Failure in maintaining any of these substances causes BBB breakdown and subsequently enhances neuroinflammation and neurodegeneration. BBB disruption is evident in many neurological conditions. Nevertheless, the majority of currently available therapies have tremendous problems with drug delivery into the impaired brain. Nanoparticle (NP)-mediated drug delivery has been considered a profound substitute to solve this problem. NPs are colloidal systems with a size range of 1-1000 nm which can encapsulate therapeutic payloads, improve drug passage across the BBB, and target specific brain areas in neurodegenerative/ischemic diseases. A wide variety of NPs has been displayed for the efficient brain delivery of therapeutics via intravenous administration, especially when their surfaces are coated with targeting moieties. Here, we discuss recent advances in the development of NP-based therapeutics for the treatment of stroke, PD, and AD, as well as the factors affecting their efficacy after systemic administration.

Background: Ruscogenin (RUS) has anti-inflammatory and antithrombotic effects, while its potential effects on deep venous thrombosis (DVT) and pulmonary embolism (PE) remain unclear. Objective: We aimed to elucidate the effects of RUS on DVT and PE induced by the inferior vena cava stenosis (IVCS) model and investigate the underlying mechanism. Methods: Male C57/BL6 mice were used to explore whether IVCS model could be complicated with deep venous thrombosis and pulmonary embolism. Then, effects of RUS on DVT and PE related inflammatory factors and coagulation were examined using H staining, ELISA, and real-time PCR. Western blot analysis was used to examine the effects of RUS on MEK/ERK/Egr-1/TF signaling pathway in PE. Results: IVCS model induced DVT and complied with PE 48 h after surgery. Administration of RUS (0.01, 0.1, 1 mg/kg) inhibited DVT, decreased biomarker D-Dimer, cardiac troponin I, N-Terminal probrain natriuretic peptide in plasma to ameliorate PE induced by IVCS model. Meanwhile, RUS reduced tissue factor and fibrinogen content of lung tissue, inhibited P-selectin and C-reactive protein activity in plasma, and suppressed the expressions of interleukin-6 and interleukin-1β in mice. Furthermore, RUS suppressed the phosphorylation of ERK1/2 and MEK1/2, decreasing the expressions of Egr-1 and TF in the lung. Conclusion: IVCS model contributed to the development of DVT and PE in mice and was associated with increased inflammation. RUS showed therapeutic effects by inhibiting inflammation as well as suppressing the activation of MEK/ERK/Egr-1/TF signaling pathway.

Background: The dissolution method for certain drugs needs specialized conditions. Dissolution testing for felodipine extended release (ER) tablets (Plendil® 5 mg) and amlodipine-indapamide fixed dose (Natrilam®, 5/1.5 mg) ER tablets requires the use of a stationary (felodipine) basket in USP Apparatus II. Objective: The study aimed to develop simple methods for Plendil® and Natrilam® without the use of a felodipine basket. Methods: The dissolution profiles obtained from different media and paddle speeds were used to compute miscellaneous dissolution parameters and were compared to those obtained from standard (existing) methods using a felodipine basket. Results: The f1, f2, and bootstrap f2 (5th % percentile) values for Plendil® 2.47, 88.17, and 54.62, respectively, and all other dissolution factors revealed similarity between standard and the selected test method with 1% Tween 20 at 50 rpm. For Natrilam®, f1 and f2 and bootstrap f2 5.13, 72.92, and 62.67, respectively, and all other dissolution parameters showed similarity of the standard and selected test method using 0.1N HCl media having 0.38 gm/L EDTA with a sinker at 100 rpm. Release of products assumed zero-order and Weibull model, respectively. Conclusion: Test dissolution methods for Plendil® and Natrilam® tablets produced equivalent dissolution profiles compared to their respective standard methods with stationary basket USP Apparatus II.

Objective: Autoimmune systemic diseases (ASD) represent a predisposing condition to COVID-19. Our prospective, observational multicenter telephone survey study aimed to investigate the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients. Methods: The study included 3,918 ASD pts (815 M, 3103 F; mean age 59±12SD years) consecutively recruited between March 2020 and May 2021 at the 36 referral centers of COVID-19 and ASD Italian Study Group. The possible development of COVID-19 was recorded by means of a telephone survey using a standardized symptom assessment questionnaire. Results: ASD patients showed a significantly higher prevalence of COVID-19 (8.37% vs. 6.49%; p<0.0001) but a death rate statistically comparable to the Italian general population (3.65% vs. 2.95%). Among the 328 ASD patients developing COVID-19, 17% needed hospitalization, while mild-moderate manifestations were observed in 83% of cases. Moreover, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular events; systemic sclerosis (SSc) patients showed a significantly higher COVID-19-related death rate compared to the general population (6.29% vs. 2.95%; p=0.018). Major adverse prognostic factors to develop COVID-19 were: older age, male gender, SSc, pre-existing ASD-related interstitial lung involvement, and long-term steroid treatment. Of note, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs. 46.99%; p=0.000), as well as the SSc patients treated with low dose aspirin (with 5.57% vs. without 27.84%; p=0.000). Conclusion: During the first three pandemic waves, ASD patients showed a death rate comparable to the general population despite the significantly higher prevalence of COVID-19. A significantly increased COVID-19- related mortality was recorded in only SSc patients’ subgroup, possibly favored by preexisting lung fibrosis. Moreover, ongoing long-term treatment with csDMARDs in ASD might usefully contribute to the generally positive outcomes of this frail patients’ population.

Background: Rheumatoid arthritis (RA) represents the most frequent form of inflammatory arthritis, affecting approximately 1% of the population worldwide. The introduction of novel therapeutic strategies targeting proinflammatory cytokines (TNF-α and interleukin-6) revolutionized the treatment of RA. This kind of treatment, although effective in a substantial portion of patients, may potentially cause many side effects. Among them, cardiovascular safety is one of the main concerns. Objectives: In the present study, we investigated the impact of treatment with anti-TNF-α and anti-IL-6 agents on heart function and levels of heart function biomarkers. Methods: To measure this, we used cardiac function biomarkers, such as NT-pro Brain Natriuretic Peptide, mid regional pro-Atrial Natriuretic Peptide, Galectin-3, and Heart-Type Fatty Acid-Binding Protein and compared them to patients treated with methotrexate as well as healthy controls. Results: Patients treated with biologics were characterized by low disease activity or were in remission. The disease activity in these groups was significantly lower than in the methotrexate group. All patients recruited for the study were characterized by normal heart function measured using echocardiography (EF>50%). With the exception of MR-proANP between tocilizumab and adalimumab (median: 1.01 vs. 0.49 nmol/L, p<0.05), we failed to observe any significant differences in biomarkers levels between groups treated with biologics. Contrary to this, patients on MTX showed higher NT-proBNP levels compared to adalimumab and healthy controls (p<0.05 for both). Striking differences have been shown in regard to H-FABP. The levels of these biomarkers were elevated in all biologics and the methotrexate group compared to healthy controls. Conclusion: As this biomarker reflects potential heart injury, we suggest that heart damage proceeds in a continuous manner in RA patients despite effective treatment and attainment of remission/low disease activity. This finding, however, should be verified in a larger cohort of RA patients to ascertain if the routine assessment of H-FABP may be useful for the detection of patients with RA who are at risk of development of heart damage.