Background: Breast cancer is one of the most common types of cancer in women, and its incidence is increasing in Iran. HER-2-positive breast cancer is invasive and often associated with poorer outcomes. Patients with this type of breast cancer can develop resistance to medications like trastuzumab. Trastuzumab-emtansine (TDM1) is a medication developed to reduce cancer cell resistance to trastuzumab. The TDM1 has been shown to decrease the incidence of death and recurrence in breast cancer. Objectives: This study aimed to evaluate the cost-utility and calculate the budget impact of TDM1 versus trastuzumab for the treatment of residual invasive HER-2-positive breast cancer. Methods: A Markov model with a lifetime horizon was developed, incorporating four health states. Women aged 45 with residual invasive HER-2-positive breast cancer entered the model. The study adopted a healthcare system perspective, with costs reported in 2021 US dollars. Discount rates of 7% for costs and 3% for utility values were applied. Utility values and transition probabilities were derived from published literature. Costs were estimated based on guidelines, expert opinions, and Iranian tariffs. Iran’s pharmacoeconomic threshold of 1085$ was used for comparison. The incremental cost-effectiveness ratio (ICER) and budget impact of TDM1 were calculated, and sensitivity analyses were conducted to assess the robustness of the model. Results: The model indicated that treatment with TDM1 resulted in a 1.59 quality-adjusted life year (QALY) increase, with an additional cost of 1408$. This was deemed cost-effective, considering Iran’s pharmacoeconomic threshold of 1085$ (calculated ICER: 886$ per QALY gained). One-way sensitivity analysis revealed that the model was sensitive to the costs of TDM1 and trastuzumab, the discount rates for utility values and costs, and the probability of achieving invasive disease-free survival (IDFS). Probabilistic sensitivity analysis showed that 59.61% of simulations fell below Iran’s pharmacoeconomic threshold, supporting the model's robustness. The budget impact analysis revealed that the additional budget required for TDM1 treatment over a three-year period was 1,120,546$ compared to trastuzumab. Conclusions: Although TDM1 imposes higher costs, it is more cost-effective than trastuzumab for the treatment of residual invasive HER-2-positive breast cancer in Iran.

Background: Folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and oxaliplatin and capecitabine (XELOX) are the most widely used chemotherapy regimens for treating metastatic colorectal carcinoma (CRC). These regimens are associated with various adverse reactions, including neuropathy and hand-foot syndrome (HFS). Silymarin, a flavonoid derived from Silybum marianum, has a wide range of biological activities. It has been used to counteract chemotherapy side effects due to its antioxidant, anti-apoptotic, and anti-inflammatory properties. Objectives: The purpose of this study was to assess the preventive effect of nano-silymarin on neuropathy and HFS induced by the FOLFOX6 and XELOX regimens. Methods: A randomized, triple-blinded, placebo-controlled clinical trial was conducted on 60 patients who were randomly assigned to receive 70 mg capsules containing 15% silymarin nano micelles twice a day after meals, starting from the first day of the first chemotherapy course and continuing for six courses of the XELOX or m-FOLFOX6 regimen. The severity of adverse effects was assessed after the third and sixth courses based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5. Results: The median CTCAE scores for HFS and neuropathy were significantly lower in the nano-silymarin group at the end of the third course (P < 0.001). However, the difference remained significant only for HFS at the end of the sixth course (P = 0.022). Additionally, the scores increased significantly in both the placebo and nano-silymarin groups during the therapy (P < 0.05). Conclusions: Nano-silymarin may be considered an adjuvant medication for the prevention of certain chemotherapy-induced adverse reactions. Further research with larger sample sizes and various doses of nano-silymarin is recommended for a more comprehensive evaluation.

Background: The positive effects of growth hormone (GH) on the endometrium, including increased endometrial blood supply and enhanced expression of cytokines associated with endometrial receptivity, have been noted. However, data on the effect of GH on the endometrium remain limited. Objectives: This study aimed to investigate the effect of intrauterine administration of GH on the IVF success rate in women with recurrent implantation failure (RIF). Methods: This randomized double-blind clinical trial was conducted on 60 infertile women under 40 years old with a Body Mass Index (BMI) below 30 kg/m², all diagnosed with RIF—defined as at least three failed pregnancies after transferring a minimum of four good-quality embryos due to unknown causes. Women with uterine malformations, Asherman syndrome, cavity-distorting lesions, severe endometriosis, or other underlying diseases were excluded. After six days of estrogen therapy, transvaginal ultrasound (TVS) was performed to measure and compare the thickness and quality of the endometrium. Participants were divided into two groups. In the intervention group, 10 units of GH were administered using an IUI catheter positioned one centimeter above the cervical os. Study outcomes included changes in endometrial thickness (ET) and quality, as well as pregnancy rates. Primary endpoints were changes in ET and quality, while secondary endpoints were pregnancy rates. Adverse drug responses were also evaluated. Results: The mean age was 34.96 ± 4.04 years, and the mean BMI was 24.89 ± 2.91 kg/m², with no significant differences in baseline variables between the study groups. The average ET on the 8th day of the cycle was 5.38 ± 0.96 mm in the intervention group and 5.20 ± 0.80 mm in the control group, showing no significant difference (P = 0.467). The ET on the day of initiating progesterone was 7.60 ± 1.03 mm in the intervention group and 7.40 ± 0.60 mm in the control group, with no significant difference (P = 0.264). The odds ratio for achieving a high-quality endometrium was 2.37 (95% CI 0.80 - 6.98, P = 0.116) for the GH group compared to the non-GH group. The odds ratio for achieving a clinical pregnancy was 3.06 (95% CI 0.54 - 17.37, P = 0.205) for the GH group compared to the non-GH group. Two cases of cervicitis were reported in the GH group. Conclusions: Intrauterine administration of GH appears to enhance endometrial receptivity in women with RIF.

Background: The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2) receptor in humans. To date, numerous SARS-CoV-2 variants, particularly those involving mutations in the RBD, have been identified. These variants exhibit differences in transmission, pathogenicity, diagnostics, and vaccine efficacy. Objectives: Although therapeutic agents are currently available to inhibit SARS-CoV-2, most provide supportive and symptomatic relief. Moreover, different variants may exhibit resistance to these treatments. This study aimed to identify a potential compound with favorable antiviral effects against SARS-CoV-2 variants. Methods: The study explored drug discovery through structure-based virtual screening of natural products (NPs) from the StreptomeDB database, targeting the ACE2-binding pocket of the SARS-CoV-2 RBD protein. The analysis included the wild-type protein (PDB ID: 6VW1) as well as the Alpha, Beta, Delta, Lambda, Omicron/BA.1, and Omicron/BA.2 variants. Results: In silico screening identified ‘Stambomycin B’ as a potential compound with the highest binding affinity. Molecular dynamics simulations of the complexes, conducted over 100 ns, confirmed the prediction that ‘Stambomycin B’ could inhibit different SARS-CoV-2 variants effectively. Conclusions: This study concludes that ‘Stambomycin B’, a macrolide compound produced by Streptomycesambofaciens, may be a candidate NP for effectively combating all mutants that occur in the binding of SARS-CoV-2 RBD to ACE2, even those that may arise in the future.

Background: Biliverdin reductase (BVR) plays a central role in bile pigment metabolism by reducing biliverdin (BV) to bilirubin (BR), a potent antioxidant that scavenges reactive oxygen species (ROS) under normal and pathological conditions. Elevated oxidative stress activates extracellular signal-regulated protein kinases 1/2 (ERK1/2) signaling, which strongly interacts with BVR’s C and D motifs, forming the BVR/ERK1/2 axis. In pathological states, increased ERK1/2 activity inhibits BVR’s ability to convert BV to BR, exacerbating oxidative damage and contributing to cardiovascular disease. Therefore, the interaction between BVR and ERK1/2 is critical in modulating oxidative stress. Objectives: This study aimed to evaluate the effects of BR and the ERK1/2 inhibitor PD-98059, both individually and in combination, on ROS levels, ERK1/2 activity, and vascular responses under normoxic and hypoxia-reoxygenation (H-R) injury conditions. Methods: Aortic rings from rats were subjected to equal distending pressure after oxidative stress induction using 22'-Azobis (2-amidinopropane) dihydrochloride (ABAP) in an organ bath. Different doses of BR were administered in combination with the ERK1/2 inhibitor PD-98059 to assess their impact on ROS depletion, vascular relaxation, and maximal effect (Emax). Results: The combination of BR and PD-98059 significantly enhanced aortic relaxation and Emax under both normoxic and H/R conditions compared to either treatment alone. Inhibiting ERK1/2 with PD-98059 appeared to upregulate BVR activity, increasing BR synthesis and reducing oxidative damage in aortic rings. Conclusions: Biliverdin reductase plays a vital role in defending against oxidative stress and endothelial dysfunction through its dual-specificity kinase activity and interaction with ERK1/2. ERK1/2 inhibition further enhances BR’s ROS-scavenging ability and vascular protective effects. Targeting the interaction between BVR and ERK1/2 holds potential as an effective therapeutic strategy for conditions characterized by excessive ROS levels, such as cardiovascular diseases.

: The inefficiency of some medications to cross the blood-brain barrier (BBB) is often attributed to their poor physicochemical or pharmacokinetic properties. Recent studies have demonstrated promising outcomes using machine learning algorithms to predict drug permeability across the BBB. In light of these findings, our study was conducted to explore the potential of machine learning in predicting the permeability of drugs across the BBB. We utilized the B3DB dataset, a comprehensive BBB permeability molecular database, to build machine learning models. The dataset comprises 7,807 molecules, including information on their permeability, stereochemistry, and physicochemical properties. After preprocessing and cleaning, various machine learning algorithms were implemented using the Python library Pycaret to predict permeability. The extra trees classifier model outperformed others when using Morgan fingerprints and Mordred chemical descriptors (MCDs), achieving an area under the curve (AUC) of 0.93 and 0.95 on the test dataset. Additionally, we conducted an experiment to train a voting classifier combining the top three performing models. The best-blended model, trained on MCDs, achieved an AUC of 0.96. Furthermore, Shapley additive exPlanations (SHAP) analysis was applied to our best-performing single model, the extra trees classifier trained on MCDs, identifying the Lipinski rule of five as the most significant feature in predicting BBB permeability. In conclusion, our combined model trained on MCDs achieved an AUC of 0.96, an F1 Score of 0.91, and an MCC of 0.74. These results are consistent with prior studies on CNS drug permeability, highlighting the potential of machine learning in this domain.

Background: This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties. Methods: Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin. Results: Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.