Drug Intolerance Research Articles

Molecular Pathogenesis and Treatment Strategies of Chronic Myeloid Leukemia (CML)

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease diagnosed in bone marrow, arising from a chromosomal translocation between chromosomes 9 and 22, resulting in the formation of fusion oncogene BCR–ABL. The product of this fusion oncogene is a new oncoprotein bcr–abl which possesses abnormal tyrosine kinase activity. In response to this, abnormal signaling pathway activation occurs, leading to cell transformation. BCR–ABL oncogene could be targeted by tyrosine kinase inhibitors (TKIs) to delay or inhibit the disease progression. Imatinib is the first drug designed against CML but resistance to this has led to the development of the second- and third generations of inhibitors that are active against many types of BCR–ABL gene mutations. However, somehow, due to disease progression, TKIs do not remain as effective. There are three well-characterized phases of CML: The chronic phase (CP), the accelerated phase, and the terminal stage which is the blast crisis (BC) stage. In the CP of CML, mature granulocytes and myeloid precursors become aggregated majorly in the bone marrow and peripheral blood. The accelerated phase is marked by increased disease severity and an increase in progenitor/precursor cell number. In the BC stage, undifferentiated blast cells grow in number. Many patients with CML are diagnosed during the CP of the disease, so the survival rate of CML is high. However, 20% of CML patients proceed to advanced stages that result in drug resistance, intolerance, and mortality. So, for proper CML treatment, drugs are needed to target multiple BCR– ABL mutations, delay or stop disease progression, and overcome resistance caused by BCR–ABL independent mechanisms, especially during advanced phases of CML. Moreover, drugs could be developed to eradicate the stem cells of CML. These targets could be achieved by understanding mechanisms of disease progression, disease relapse, and drug resistance by utilizing high throughput molecular genetics, cell biology and immunology techniques.

Comparison of Long-Term Outcome between Imatinib and Dasatinib Prophylaxis after Allogeneic Stem Cell Transplantation in Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia-a Multi-Center Retrospective Study

Background: Though the prognosis of Philadelphia-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has been improved since the introduction of tyrosine kinase inhibitors (TKIs) and combined with allogeneic stem cell transplantation (allo-HSCT), relapse after HSCT remains a concern. Prophylactic TKIs after allo-HSCT seemed a promising strategy to prevent relapse. But the optimal choice of the agent is still obscure.Methods: We retrospectively analyzed the clinical data of Ph-positive ALL patients who underwent allo-HSCT in CR1 from 6 medical centers in China between September 2010 and October 2021. Patients were divided into two cohorts according to different choice of TKI after allo-HSCT, namely Ima cohort with imatinib prophylaxis and Das cohort with dasatinib prophylaxis. Survival and safety outcomes of two cohorts were compared, and prognostic factors were determined by univariate and multivariate analyses.Results: One hundred and forty-one patients, with median age of 37 years (range, 14-61 years), were included, of whom 91 were in Ima cohort and 50 were in Das cohort. After median follow-up of 50.6 months, 5-year cumulative relapse rate (CIR), non-relapse mortality rate (NMR), leukemia-free time (LFS) and overall survival (OS) in Ima and Das cohort were 16.1% and 12.5%; 5.2% and 9.8%; 78.8% and 77.6%; 86.5% and 77.6%, respectively, with no significant difference. Mild cGVHD was higher in Das cohort compared to Ima cohort, while the total, moderate or severe cGVHD were similar. The most common adverse event was neutropenia (66.4%). Das cohort owned higher incidence of gastrointestinal bleeding and gastrointestinal reaction than Ima cohort. The proportion of patients treated on schedule was 30% in Das cohort, lower than that of in Ima cohort (p<0.001). Drug intolerance was the main reason for not completed treatment as intended.Conclusions: For patients with Ph-positive ALL receiving allo-HSCT in CR1, imatinib prophylaxis after transplantation could obtain the same long-term outcome compared to dasatinib, showing better tolerance.

Efficacy and Safety of Avatrombopag on Thrombocytopenia after Chemotherapy in Acute Leukaemia

Background: Thrombocytopenia following chemotherapy is a common and serious complication that leads to an increased risk of bleeding and poor prognosis for patients with acute leukaemia. Current therapeutic strategies consist of platelet transfusion, recombinant human interleukin-11(rhIL-11) and recombinant human thrombopoietin (rhTPO) injection, but these strategies are not satisfactory for some patients and the treatment remains challenging. Avatrombopag is a novel thrombopoietin receptor agonist, which had been approved for thrombocytopenia in patients with chronic liver disease who are scheduled to undergo a surgery in the USA, Europe, and China, and in patients with chronic immune thrombocytopenia who were unresponsive to previous treatments in the USA and Europe. This study aims to determine the efficacy and safety of avatrombopag on thrombocytopenia after chemotherapy of acute leukaemia, and to increase the evidence for clinical use of avatrombopag. Methods: The clinical data of 24 acute leukaemia patients with grade 3/4 chemotherapy-induced thrombocytopenia (CIT) for 3-28 days were collected from February 2022 to February 2023. All patients received avatrombopag orally at a dose of 40 mg / day. Platelet (PLT) transfusion was allowed when the platelet level was less than 20×10 9/L or with bleeding events. If platelet count increased to 100 ×10 9/L or 50 ×10 9/L more than baseline, which was defined as complete response (CR), treatment of avatrombopag was stopped. Results: The median age of 24 patients with CIT was 38 (range 17‒69) years, with 14 patients diagnosed with acute myeloid leukemia (AML), 9 patients diagnosed with acute lymphoblastic leukemia (ALL), and 1 patient diagnosed with mixed phenotype acute leukemia (MPAL). Chemotherapy regiments for patients with AML included decitabine combined with venetoclax (n=5), decitabine combined with arabinoside (n=3), arsenic trioxide combined with retinoic acid (n=3), azacytidine combined with venetoclax (n=2), azacytidine combined with medium-dose arabinoside (n=1). Chemotherapy regiments for patients with ALL included CD19 specific CAR-T cells (n=3), decitabine (n=2), blinatumomab (n=2), IVP (idarubicin, vindesine, and prednisone) (n=1), azacytidine combined with venetoclax and chidamide (n=1). Chemotherapy regiment for the patient with MPAL was decitabine combined with venetoclax (n=1). At baseline, 10 patients experienced grade 3 thrombocytopenia after chemotherapy, while 14 patients experienced grade 4 thrombocytopenia after chemotherapy. The median lowest platelet count was 19×10 9/L (range 1-47×10 9/L). During the treatment period, 14 patients received platelet transfusion. The median time to reach the CR standard was 6 (range 3-26) days, and no patients stopped treatment due to side effect or drug intolerance. Compared with using avatrombopag before, the levels of platelet count were significantly increased ( P=0.000 1). The optimal platelet count of 22 patients reached the standard of CR after 7 days of drug withdrawal. Conclusion: Avatrombopag is effective on increasing platelet counts in patients with acute leukaemia after chemotherapy, with a good safety profile. It is a suitable therapeutic option for thrombocytopenia after chemotherapy.

Phase II Trial of Ibrutinib in Previously Untreated High-Risk Smoldering Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) patients usually require immediate therapy, however about 20% of newly diagnosed MCL patients can be initially observed. A subgroup of patients who are suitable for initial observation but exhibit high-risk features are of particular concern as they have a propensity to progress. We consider these patients as high-risk smoldering MCL (defined below). Generally, these patients are observed without systemic therapy for 18-24 months. We investigated the impact of single-agent ibrutinib on time to progression for these patients who would otherwise be observed. Methods: This is a single center, single arm, investigator-initiated phase 2 clinical trial (NCT03282396). High-risk smoldering MCL included one or more of the following criteria: non-blastoid/pleomorphic variant, Ki-67 of 15-30%, white blood cell count of 15-30 x 10^9/L, lymph nodes ≤5 cm, TP53 mutated or wild type, del17p, MYC positive, complex karyotype, presence of KMT2D, BIRC3, or ≥1 other somatic mutations, and were asymptomatic without any clinical indication to start systemic therapy. Major exclusion criteria included significant disease-related symptoms, blastoid/pleomorphic variants, Ki-67 >30%, bulky tumors >5 cm. Patients received ibrutinib 560 mg P.O. daily in 28-day cycles and continued until progression, transformation, drug intolerance, or up to 5 years. The primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, response rate, and duration of response (DOR). Response was measured using the Lugano criteria. It is expected that the current trial will achieve a median PFS time of about 18 months, which would be an improvement over PFS reported on high-risk patients under a watch and wait approach. The median follow-up time was 23.4 months. Results: Twenty patients were enrolled (Table 1). The median age was 60.5 years (range 38-79). Most were male (n=15/20). At baseline, 13 patients (65%) had bone marrow involvement and 15 patients (75%) had gastrointestinal tract involvement. Seven patients (35%) had TP53 alterations. One patient was not evaluable for response due cessation of therapy after less than 1 cycle due to new onset atrial fibrillation. Among 19 evaluable patients, the best overall response rate was 94.7% (n=18/19). Of those who had a positive PET at baseline and were evaluable for PET response, 92.9% (n=13/14) achieved a PET complete response (CR). Of those with bone marrow involvement at baseline, 30.7% (n=4/13) achieved CR by flow cytometry. Of those with baseline gastrointestinal tract involvement, 33.3% (n=5/15) achieved histologically confirmed CR. The median number of cycles received was 16 (range 0-32). The median PFS and DOR were not reached. Seven patients discontinued therapy: atrial fibrillation (n=3), progressive disease (n=1), infection (n=1), lung cancer (n=1). The most frequent grade 3 toxicities were diarrhea (n=2, 10%), atrial fibrillation (n=1, 5%), infection (n=1, 5%), mucositis (n=1, 5%), and syncope (n=1, 5%). No grade 4 toxicities occurred. No deaths on study occurred. Conclusions: Ibrutinib demonstrated significant efficacy with manageable toxicities in previously untreated patients with high-risk smoldering MCL.

ALA-PDT shortens the course of antibiotic therapy for skin infection caused by Mycobacterium marinum

BackgroundRecently, the number of cases of Mycobacterium marinum infection has increased. Due to the nonspecific clinical manifestations and lack of standardized treatment guidelines, these infections are often misdiagnosed and are challenging to treat. MethodsIn this study, four patients had M. marinum skin infections accompanied by a high-risk exposure history and were diagnosed by bacterial culture and gene chip. Two patients were treated with antibiotic therapy alone, and the other two patients were treated with 5-aminolevulinic acid photodynamic therapy (ALA-PDT) combined with antibiotics. ResultsAll four patients enrolled in the study were cured with 100 % efficacy. Two patients were cured after receiving two active antibiotics for 4 months. The other two patients, having considered the drug resistance and intolerance described above, were cured after receiving two active antibiotics for 1–1.5 months along with combination therapy with ALA-PDT. ConclusionCombination therapy with ALA-PDT and antibiotics was chosen to shorten the duration of antibiotic treatment and reduce the occurrence of adverse reactions.

Drug Allergy in Women

Across all settings, women self-report more drug allergies than do men. Although there is epidemiologic evidence of increased drug allergy labeling in postpubertal females, the evidence base for female sex as a risk factor for true immune-mediated drug hypersensitivity reactions (DHRs), particularly in fatal drug-induced anaphylaxis, is low. A focus on the known immunologic mechanisms described in immediate and delayed DHR, layered on known hormonal and genetic sex differences that drive other immune-mediated diseases, could be the key to understanding biological sex variations in DHR. Particular conditions that highlight the impact of drug allergy in women include (1) pregnancy, in which a drug allergy label is associated with increased maternal and fetal complications; (2) multiple drug intolerance syndrome, associated with anxiety and depression; and (3) female-predominant autoimmune medical conditions in the context of mislabeling of the drug allergy or increased underlying risk. In this review, we describe the importance of drug allergy in the female population, mainly focusing on the epidemiology and risk, the mechanisms, and the associated conditions and psychosocial factors. By performing a detailed analysis of the current literature, we provide focused conclusions and identify existing knowledge gaps that should be prioritized for future research.

Review on the Drug Intolerance and Vaccine Development for the Leishmaniasis.

Leishmaniasis is one of the Neglected Tropical Diseases (NTDs), a zoonotic disease of vector-borne nature that is caused by a protozoan parasite Leishmania. This parasite is transmitted by the vector sandfly into the human via a bite. Visceral leishmaniasis (VL), also called kala-azar, is the most fatal among the types of leishmaniasis, with high mortality mostly spread in the East Africa and South Asia regions. WHO report stated that approximately 3.3 million disabilities occur every year due to the disease along with approximately 50,000 annual deaths. The real matter of concern is that there is no particular effective medicine/vaccine available against leishmaniasis to date except a few approved drugs and chemotherapy for the infected patient. The current selection of small compounds was constrained, and their growing drug resistance had been a major worry. Additionally, the serious side effects on humans of the available therapy or drugs have made it essential to discover efficient and low-cost methods to speed up the development of new drugs against leishmaniasis. Ideally, the vaccine could be a low risk and effective alternative for both CL and VL and elicit long-lasting immunity against the disease. There are a number of vaccine candidates at various stages of clinical development and preclinical stage. However, none has successfully passed all clinical trials. But, the successful development and approval of commercially available vaccines for dogs against canine leishmaniasis (CanL) provides evidence that it can be possible for humans in distant future. In the present article, the approaches used for the development of vaccines for leishmaniasis are discussed and the progress being made is briefly reviewed.

Two cases of acute‐onset cystoid macular edema and serous retinal detachment associated with combined use of encorafenib and binimetinib for advanced melanoma: A possible confounding risk for drug intolerance

AbstractWhile combined use of BRAF/MEK inhibitors has elicited dramatic clinical efficacy in incurable melanoma, drug‐associated retinopathy has become an emerging adverse event. We present two Japanese men with advanced melanoma who developed visual impairment due to serous retinal detachments (SRDs) with cystoid macular edema (CME) immediately after initial administration of encorafenib/binimetinib, a BRAF and MEK inhibitor. One case had drug‐intolerable retinopathy on repeat dosing. Both cases were switched to another BRAF/MEK inhibitors, dabrafenib/trametinib, with no recurrence of SRDs. Co‐existing CME may be a confounding risk for the early development of SRDs with encorafenib/binimetinib therapy, providing attention during drug administration.

Anesthetic Management of Transoral Odontoidectomy in a Child with Multiple Drugs Intolerance Syndrome

AbstractPatients with an adverse reaction to more than three groups of drugs have multiple drug intolerance syndrome (MDIS). Regional anesthesia can be an attractive alternative when patients presenting for surgery are diagnosed with MDIS for opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Moreover, supplementary regional anesthetic techniques reduce exposure to multiple anesthetic medications, reducing the incidence of allergic reactions. We report the case of a pediatric patient diagnosed with MDIS presenting for transoral odontoidectomy and tracheostomy, wherein regional anesthesia techniques aided us in providing perioperative analgesia and maintaining hemodynamic stability.

A masquerade of recurrent anaphylaxis.

Background: We present a case of a 37 year old man with a history of human immunodeficiency virus, latent syphilis, anxiety, posttraumatic stress disorder. attention deficit/hyperactivity disorder, multiple drug intolerance syndrome who presented with concerns of recurrent episodes of rash and respiratory symptoms with questionable "anaphylaxis" episodes without clear etiology or known trigger. Methods: To evaluate some of the potential causes of recurrent anaphylaxis in our patient. Further evaluation through laboratory analysis and ultimately direct visualization of the patient's vocal cords by laryngoscopy assisted in the final diagnosis. Results: Inappropriate adduction of the vocal cords was observed during an acute reaction. Conclusion: The patient's presentation was consistent with inducible laryngeal obstruction and highlights the importance of confirming a suspected diagnosis of anaphylaxis and keeping a broad differential when establishing an etiology.

Allicin, an Emerging Treatment for Pulmonary Arterial Hypertension: An Experimental Study.

We assessed whether allicin, through its antihypertensive and antioxidant effects, relieves vascular remodeling, endothelial function, and oxidative stress (OS), thereby improving experimental pulmonary arterial hypertension (PAH). Allicin (16 mg/kg) was administered to rats with PAH (monocrotaline 60 mg/kg). Allicin encouraged body weight gain and survival rate, and medial wall thickness and the right ventricle (RV) hypertrophy were prevented. Also, angiotensin II concentrations in the lung (0.37 ± 0.01 vs. 0.47 ± 0.06 pmoles/mL, allicin and control, respectively) and plasma (0.57 ± 0.05 vs. 0.75 ± 0.064, allicin and control respectively) and the expressions of angiotensin-converting enzyme II and angiotensin II type 1 receptor in lung tissue were maintained at normal control levels with allicin. In PAH rats treated with allicin, nitric oxide (NO) (31.72 ± 1.22 and 51.4 ± 3.45 pmoles/mL), tetrahydrobiopterin (8.43 ± 0.33 and 10.14 ± 0.70 pmoles/mL), cyclic guanosine monophosphate (5.54 ± 0.42 and 5.64 ± 0.73 pmoles/mL), and Ang-(1-7) (0.88 ± 0.23 and 0.83 ± 0.056 pmoles/mL) concentrations increased in lung tissue and plasma, respectively. In contrast, dihydrobiopterin increase was prevented in both lung tissue and plasma (5.75 ± 0.3 and 5.64 ± 0.73 pmoles/mL); meanwhile, phosphodiesterase-5 was maintained at normal levels in lung tissue. OS in PAH was prevented with allicin through the increased expression of Nrf2 in the lung. Allicin prevented the lung response to hypoxia, preventing the overexpression of HIF-1α and VEGF. Allicin attenuated the vascular remodeling and RV hypertrophy in PAH through its effects on NO-dependent vasodilation, modulation of RAS, and amelioration of OS. Also, these effects could be associated with the modulation of HIF-1α and improved lung oxygenation. The global effects of allicin contribute to preventing endothelial dysfunction, remodeling of the pulmonary arteries, and RV hypertrophy, preventing heart failure, thus favoring survival. Although human studies are needed, the data suggest that, alone or in combination therapy, allicin may be an alternative in treating PAH if we consider that, similarly to current treatments, it improves lung vasodilation and increase survival. Allicin may be considered an option when there is a lack of efficacy, and where drug intolerance is observed, to enhance the efficacy of drugs, or when more than one pathogenic mechanism must be addressed.

Efficacy and safety of baroreflex activation therapy for heart failure with reduced ejection fraction: systematic review.

Baroreflex activation therapy (BAT) is a possible adjuvant treatment for patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy and may be an alternative therapy in patients with contraindications or drug intolerance. Our aim was to evaluate the efficacy and safety of BAT in patients with HFrEF. The protocol for this study was registered with PROSPERO (CRD42022349175). Searches were conducted using MEDLINE, preMedLine (via PubMed), EMBASE, Cochrane Library, Web of Science, Trip Medical Database, WHO International Clinical Trials Registry, and ClinicalTrials.gov. We included randomized controlled trials that compared the effects of BAT with pharmacological treatment. We assessed the risk of bias of each study using the Cochrane RoB2 tool and the certainty of the results using the GRADE approach. We performed a meta-analysis of treatment effects using a fixed-effects or random-effects model, depending on the heterogeneity observed. Two studies were included in the meta-analysis (HOPE4HF and BeAT-HF). The results showed that BAT led to statistically significant improvements in New York Heart Association functional class (relative risk 2.13; 95% confidence interval [CI, 1.65 to 2.76]), quality of life (difference in means -16.97; 95% CI [-21.87 to -12.07]), 6min walk test (difference in means 56.54; 95% CI [55.67 to 57.41]) and N-terminal probrain natriuretic peptide (difference in means -120.02; 95% CI [-193.58 to -46.45]). The system- and procedure-related complication event-free rate varied from 85.9% to 97%. The results show that BAT is safe and improves functional class, quality of life and congestion in selected patients with HFrEF. Further studies and long-term follow-up are needed to assess efficacy in reducing cardiovascular events and mortality.

CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44-88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56-96), and OS from HSCT at 1 year was 80% (95% CI: 50-93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.

Reasons for antiretroviral switching in Colombia: A retrospective cohort study.

Long-term use of antiretroviral therapy (ART) for HIV infection might lead to the necessity of switching regimens. We aimed to analyze the reasons for the ART switch, the time-to-switch of ART, and its associated factors in a Colombian cohort. We conducted a retrospective cohort in 20 HIV clinics, including participants ≥18years old with confirmed HIV infection who underwent an ART switch from January 2017 to December 2019 with at least 6 months of follow-up. A time-to-event analysis and an exploratory Cox model were performed. 796 participants switched ART during the study period. The leading cause of ART switch was drug intolerance (n = 449; 56.4%) with a median time-to-switch of 12.2months. The longest median time-to-switch was due to regimen simplification (42.4months). People ≥50years old (HR = 0.6; 95% CI (0.5-0.7) and CDC stage 3 at diagnosis (HR = 0.8; 95% CI (0.6-0.9) had less hazard for switching ART over time. In this Colombian cohort, drug intolerance was the main cause of the ART switch, and the time-to-switch is shorter than reports from other countries. In Colombia, it is crucial to apply current recommendations for ART initiation to choose regimens with a better tolerability profile.

Role of substance P in the pathogenesis of chronic urticaria

Chronic urticaria (CU) is a serious issue in clinical allergology. Exact pathogenesis of diseases is unknown despite a fairly large number of studies. From clinical view, CU manifests as wheals and/or angioedema, lasting for more than 6 weeks. It is classified into spontaneous (without obvious triggers) and induced CU (in cases of evident physical and chemical stimuli). It is quite difficult to reveal its cause. Most often, the patients refer to specific foods as a trigger factor. Stress is the second leading cause of CU after breaking the diet. Mental or emotional stress has been shown to cause degranulation of mast cells (MC) and histamine release. Substance P (SP) is a neurotransmitter, which underlies neuroimmune inflammation, being considered the most informative marker of CU. The purpose of our study was to assess a role of SP in the CU pathogenesis and to determine the relationship of SP with known urticaria triggers and comorbidities.
 We examined 97 patients with CU and 68 apparently healthy individuals matched by sex and age. The levels of histamine and substance P (SP) were determined in blood serum by enzyme immunoassay. The patients were classified into groups, depending on the history of food and drug intolerance, presence of concomitant autoimmune thyroiditis (AIT), influence of stress as a trigger for CU.
 When analyzing the average levels of histamine and SP in the group of patients suffering from CU, compared with the control group, no significant correlations were found. We detected an almost 3-fold increase of histamine levels in the patients suffering from AIT (28.25 ng/mL versus 83.61 ng/mL). However, when assessing the level of histamine in patients with CU and with a history of food and drug intolerance, trigger stress and AIT, the average values of the indicator did not show significant differences. Meanwhile, when assessing the SP index in patients with a history of drug, food intolerance, AIT and stress as a trigger for CU, we have found a significant increase in SP in the patients when compared with control group (p 0.05).
 Our results confirm the neuroimmune inflammation system to be involved in genesis of mast cell activation in CU patients. Further studies are required in order to discern a specific phenotype of stress-induced CU and determine the opportunities for its psychopharmacological correction.

Polymer-based nanosystems and their applications in bone anticancer therapy.

The mortality rate of bone cancer has witnessed a substantial reduction in recent years, all thanks to the advent of advanced cancer treatment modalities such as surgical intervention, radiation, and chemotherapy. Nevertheless, these popular modalities come with a set of clinical challenges, including non-specificity, side effects, and drug intolerance. In recent years, polymer-based nanosystems have emerged as a promising solution in bone anti-cancer therapy by virtue of their unique physical and chemical properties. These nanosystems can be tailored for use in different drug release mechanisms for therapeutic implementations. This review delves into the efficacy of these therapy applications in bone cancer (with a focus on one of the most common types of cancers, Osteosarcoma) treatment and their correlation with the properties of polymer-based nanosystems, in addition to their interaction with the tumor microenvironment and the biological milieu.

Efficacy and safety of cilostazol-based triple antiplatelet therapy compared with clopidogrel-based dual antiplatelet therapy in patients with acute ST-elevation myocardial infarction undergoing percutaneous coronary intervention: A multicenter, randomized, open-label, phase 4 trial

Previous studies reported that compared to conventional dual antiplatelet therapy (DAT; aspirin+clopidogrel), triple antiplatelet therapy (TAT), involving the addition of cilostazol to DAT, had better clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). However, the optimal duration of TAT is yet to be determined. In total, 985 patients with STEMI who underwent primary percutaneous coronary intervention (PCI) with drug-eluting stents (DESs) were prospectively enrolled in 15 PCI centers in South Korea and China. We randomly assigned patients into 3 groups: DAT (aspirin and clopidogrel for 12 months), TAT 1M (aspirin, clopidogrel, and cilostazol for 1 month), and TAT 6M (aspirin, clopidogrel, and cilostazol for 6 months). The primary endpoint was 1-year major adverse cardiovascular events (MACEs), defined as a composite of all-cause death, recurrent myocardial infarction, stroke, or repeat revascularization. The primary endpoint did not differ among the 3 groups (8.8% in DAT, 11.0% in TAT 1M, and 11.6% in TAT 6M; hazard ratio for TAT 1M vs DAT, 1.302; 95% confidence interval [CI], 0.792-2.141; P=.297; hazard ratio for TAT 6M vs DAT, 1.358; 95% CI, 0.829-2.225; P=.225). With respect to in-hospital outcomes, more bleeding events occurred in the TAT group than in the DAT group (1.3% vs 4.7% vs 2.6%, P=.029), with no significant differences in major bleeding events. Additionally, the TAT group had a higher incidence of headaches (0% vs 1.6% vs 2.6%, P=.020). The addition of cilostazol to DAT did not reduce the incidence of 1-year MACEs compared with DAT alone. Instead, it may be associated with an increased risk of drug intolerance and side effects, including in-hospital bleeding and headaches.

Approaches to the diagnosis of the Churg-Strauss syndrome

Churg-Strauss syndrome or eosinophilic granulomatosis with polyangiitis is a rare congenital autoimmune disease characterized by pathologies in the development of various organs. It develops either as a result of a genetic mutation (mutation of the CHD7 gene), or under the influence of external factors. The disease was first described in 1951 by Jacob Churg and Lotte Strauss as «allergic granulomatosis ». As a separate disease, the syndrome was isolated in 1990. The frequency of the disease ranges from 2 to 8 cases per 1 million people. There are no gender differences in the incidence of men and women. The disease begins to appear around the age of 38–49 years. The development of the syndrome goes through three stages. At the initial stage, allergic manifestations develop: rhinitis, sinusitis, hay fever, bronchial asthma, and drug intolerance. At the second stage, a hypereosinophilic syndrome, clinically manifested in Loeffler's syndrome, eosinophilic pneumonia, and eosinophilic gastroenteritis, develops. At the third stage, signs of systemic vasculitis appear.

Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Diabetes and Coronary Artery Disease: Translating the Benefits of the Molecular Mechanisms of Gliflozins into Clinical Practice.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed for the treatment of diabetes due to their antihyperglycemic activity. However, in the light of the most recent clinical studies, they are revolutionizing the approach to cardiovascular disease in patients with and without diabetes. We aimed to generate real-world data about the use of SGLT2i in patients with T2DM and coronary artery disease (CAD), focusing on their effectiveness in glycemic control, adherence, long-term efficacy, and safety outcomes. On the basis of the inclusion and exclusion criteria, 143 patients were enrolled. Patients were treated with canagliflozin (n = 33 patients; 23%), dapagliflozin (n = 52 patients, 36.4%), empagliflozin (n = 48 patients; 33.6%), or ertugliflozin (n = 10 patients; 7%) as monotherapy or in combination with other antidiabetic drugs. All patients performed a clinical visit, and their medical history, blood sampling, and anthropometric parameters were measured at discharge and at 1-year follow-up. The reduction in HbA1c % value at 12 months was significant (8.2 vs. 7.4; p < 0.001). Trends in body weight and body mass index also confirmed the positive effect of the treatment (p < 0.0001), as did the reduction in abdominal adiposity (expressed via waist circumference). At 1-year follow-up, 74.1% of patients were adherent to the treatment, and 81.1% were persistent to the treatment. A total of 27 patients (18.8%) had to discontinue treatment early due to drug intolerance caused by genitourinary infections (11.9%), the drub being permanently ineffective (HbA1c not at target or decreasing: 4.9%), or because of expressing. a desire not to continue (2%). No major drug-related adverse events (diabetic ketoacidosis, Fournier's gangrene, lower-limb amputations) occurred at follow-up, while MACE events occurred in 14 patients (9.8%). In real-world patients with T2DM and CAD, SGLT2i have been effective in long-term glycemic control and the improvement in anthropometric indices with good tolerance, high adherence, persistence to treatment, and no major adverse events at 1-year follow-up.

Features of diagnostic search and experience inthetreatment of chronic urticaria in obese patients withpulmonary pathology

Background. In recent decades, along with the growth of allergic diseases, there has been a progressive increase in the number of people with overweight of varying severity, as evidenced by numerous epidemiological studies. Therefore, both allergies and obesity are among the global problems of modern healthcare due to their high prevalence and medical and social significance. The purpose of the study was analysis of the etiological factors of chronic urticaria (CU) in obese patients with pulmonary pathology, optimization of diagnosis and treatment of CU for further planning of preventive measures. Materials and methods. We examined 250 patients who applied for medical care to the regional clinical hospital in Chernivtsi and had CU associated with pulmonary pathology and obesity. Based on the analysis of the obtained data, a group of 140 patients was formed for further clinical and anamnestic examination: analysis of the anamnesis, determination of the severity of urticaria, assessment of quality of life, control of urticaria symptoms, general clinical laboratory studies, tests for verification of urticaria. Allergy testing was carried out when the patient’s anamnestic data indicated its expediency. The survey was carried out for one month and included a diagnostic period and 3 consultations every 7–10 days. Results. Among the causes of CU in patients with pulmonary disease, drug intolerance and parasitic infection dominate. Polyetiology is observed in 60% of cases. Differences in CU in obese patients are the long-term persistence of urticaria or other elements of the rash, the lack of effectiveness of therapy with the second- and third-generation antihistamines and glucocorticosteroids. Conclusions. The results obtained indicate a positive effect of the quinuclidine derivative quifenadine for the treatment of CU in patients with pulmonary pathology and obesity. Complete and significant effects were obtained in 91.43% of patients. The worst results (8.57%) were demonstrated by patients with the etiological significance of chemical factors (including occupational ones), which is associated with more problematic compliance with the elimination regimen in this category of patients.