Pakistan journal of pharmaceutical sciences最新文献

We report a new scoring method for rating the performance of ligands on same protein, using their extensive dynamic flexibility properties, binding with protein and impact on receptor protein. Based on molecular dynamics (MD), this method is more accurate than single-point energy calculations. This method identified an ideal FDA-approved drug as β-tubulin microtubule inhibitor with improved attributes compared to commercial microtubule disassembly inhibitor, Paclitaxel (PTX). We started with virtual screening (VS) of FDA-approved drugs inside PTX's binding pocket (A) of human β-tubulin protein. Screened ligands (>80% score) were evaluated for non-permeation through blood-brain barrier (BBB) as targets were body cancers, gastrointestinal absorption, Lipinski, non-efflux from central nervous system (CNS) by p-glycoprotein (Pgp), and ADMET analysis. This identified FDA-approved Naloxegol drug with superior attributes compared to PTX. Pocket (A) specific docking of chain length variable derivatives of Naloxegol gave docked poses that underwent MD run to give a range of properties and their descriptors (RMSD, RMSF, RoG, H-bonds, hydrophobic interaction and SASA). QSPR validated that MD properties dependent upon [-CH₂-CH₂-O-]_n=0-7 chain length of Naloxegol. MD data underwent normalization, PCA analysis and scoring against PTX. One Naloxegol derivative scored higher than PTX as a potential microtubule disassembly inhibitor.

The present study aimed to assess the antidepressant profile of fluoxetine in the rats exhibiting lorazepam-induced abusive effects in place preference paradigm. Lorazepam, a benzodiazepine is commonly utilized for treating anxiety, panic attacks, status epilepticus, depressive disorders and sedation. Despite its therapeutic benefits, repeated lorazepam administration can lead to dependence, possibly involving heightened dopaminergic neurotransmission. Additionally, an important role is played by serotonergic system in anxiety and addiction pathophysiology and treatment. The study aimed to examine fluoxetine's impact on lorazepam-induced addiction, as fluoxetine, a selective serotonin reuptake inhibitor, enhances 5-HT availability by inhibiting its reuptake in neurons. Behavioral parameters, including growth rate, food intake, behaviors in forced swim test, open field, light dark box test, Skinner's box and conditioned place preference, were monitored in rats subjected to oral lorazepam (2 mg/kg) and fluoxetine (1mg/kg) administration. Neurochemical analysis suggests that fluoxetine enhances serotonin levels, which counteracts the dopamine-driven addictive effects of lorazepam within the caudate and nucleus accumbens. This supports the notion that serotonin-dopamine interplay facilitates mitigate dependency by stabilizing the reward pathways following lorazepam administration.

Hydroxychloroquine, used initially as an anti-malarial drug, is now recognized for its anti-tumor effects in a range of human cancers. Nevertheless, there has been limited attention given to the molecular mechanisms of anti-tumor action of hydroxychloroquine. Here, we investigated the anti-tumor effect of hydroxychloroquine in human A549 cells and further analyzed the potential molecular mechanisms involved. Hydroxychloroquine was found to effectively inhibit the growth of A549 cells. This inhibition was observed to be both dose-dependent and time-dependent. Moreover, in a tumor xenograft mouse model, hydroxychloroquine remarkably suppressed tumor growth. Mechanistically, treatment with hydroxychloroquine led to the inhibition of phosphorylation in JNK, STAT3 and AKT. This biochemical interference subsequently induced G1 cell cycle arrest and promoted mitochondrial-mediated apoptosis in A549 cells. The findings from this study offered robust evidence supporting the use of hydroxychloroquine as a treatment for non-small cell lung cancer (NSCLC). Consequently, hydroxychloroquine emerges as a potential therapeutic agent for the treatment of this cancer.

Capecitabine is an oral pro-drug of 5-flourouracil used in treatment of different cancers. It has cardiotoxicity incidence of 3-35%, which can be significant enough to cause myocardial infarction. To evaluate the efficacy of glyceryl trinitrate in reducing cardiac events when given concomitantly with capecitabine for at least 3 months in various tumors. A quasi-experimental study was conducted in Hameed Latif Hospital from January 2019 to December 2023. A total of 65 patients with various malignancies and ECOG 0-2 were included. Glyceryl trinitrate was given before capecitabine for at least 3 cycles with 2.6 mg dosage twice a day. Cardiotoxicity was assessed after each 21-days cycle by taking history and ECG. Echocardiogram was done at 3-month follow up Patients aged from 49 to 86 years. Adverse events were noted in 3 (4.6%) patients. Two patients (3.1%) suffered from angina (grade 2 cardiotoxicity) while 1 (1.5%) suffered from a myocardial infarction (grade 3 cardiotoxicity). On stratification, only treatment in adjuvant setting (p<0.001) was found to be a possible risk factor. Glyceryl trinitrate may have potential to be used concomitantly with capecitabine to reduce the frequency of serious cardiac events in cancer patients. However, further studies are needed.

We studied the effectiveness of Atractylodis Macrocephalae Rhizoma Tianma soup mixed with peach kernel safflower Fried in treating acute cerebral infarction. 96 patients were divided into two groups and received routine treatment as per hospital guidelines. 48 patients were given the herbal mixture while the rest were not. A comparison of inflammatory factors, coagulation, liver and kidney function showed significant differences between the two groups on day 14. The observation group had higher APTT, PT, TT values and ALP levels, but lower BUN levels compared to the control group. The observation group had significantly higher ALP levels and GGT levels on day 14 compared to the control group, while Cr and BUN levels were lower. This difference was statistically significant (P<0.05). The peach kernel safflower fried and Attractylodis Macrocephalae Rhizoma Tianma soup combination reduces inflammation in acute cerebral infarction patients, improving clinical symptoms without any reported adverse reactions.

To assess the effect of subconjunctival injection of anti-VEGF bevacizumab in the management of dry eye disease in a tertiary care hospital. In this quasi-experimental trial 150 eyes of 75 patients were selected using non-probability consecutive sampling technique. Detailed clinical examination was performed, the ocular surface disease index (OSDI) questionnaire score, tear film break-up time (TBUT) and Schirmer test 2 were measured and compared pre and post injection. Six patients were excluded and sixty-six patients were included having the mean age was 65.3 (SD=±10.2) years, 50% were aged 66-83 years old, 65.2% were female. Pre injection OSDI score was 30.3 (SD=±2.79), whereas post injection it was 20.2 (SD=±3.01). Pre injection TBUT was 3.0 (SD=±0.30), whereas post injection it was 5.17 (SD=±0.40). Pre injection Schirmer 2 test was 7.97 (SD=±0.51), whereas post injection it was 10.5 (SD=±0.50). Ten patients suffered mild subconjunctival hemorrhage which resolved spontaneously. Three patients were lost to follow up. Subconjunctival injection of anti-VEGF agent bevacizumab can offer a modern and safe solution in patients suffering from dry eye disease nevertheless more trials with large number of patients and longer follow up durations are required for widespread adaptation.

Glioblastoma multiforme is the most aggressive and invasive primary brain tumor in adults and its prognosis and survival rate remain poor. Despite substantial improvements in therapy, the 5-year survival rate of glioblastoma patients remains low. Sesquiterpenes have previously been found to be effective in inhibiting the proliferation and growth of breast, gastric and lung cancer cells. Owing to their efficacy, sesquiterpenes have been used in various clinical trials. In the present study, we investigated the anticancer efficacy of a well-known sesquiterpene, Zingiberene, isolated from Zingiber officinale in C6 glioblastoma cells. Zingiberene suppresses the growth and proliferation of C6 cells. Upon treatment of C6 cells with zingiberene, nuclear fragmentation and ROS were qualitatively enhanced compared to untreated control cells. The levels of caspase-3 were also significantly reduced (p<0.01), with a concomitant decline in the mRNA expression of Bax and Bcl-2. On the basis of molecular docking studies, Zingiberene demonstrated good binding energy score of -6.8 and -5.5 Kcal/mol towards Bax and Bcl-2 proteins, respectively. Based on these observations, it was inferred that zingiberene has potential as a plausible therapeutic agent against glioblastoma cells. Detailed mechanistic studies are needed to substantiate and establish the anticancer effects of zingiberene against glioblastoma cells.

Lycorine (LYC), as a natural alkaloid, possesses various significant biological activities. This study aims to investigate the impact and underlying mechanisms of LYC on the malignant progression of hepatocellular carcinoma (HCC). The levels of miR-224-5p, collectin subfamily member 10 (COLEC10) and inflammatory factors were quantified by RT-qPCR. The levels of COLEC10 and EMT relevant proteins were identified by Western blotting. Effects of LYC on the biological behaviors of HCC cells were assessed. The Dual-Luciferase reporter assay was used to verify the targeting relationship between miR-224-5p and COLEC10. Additionally, A subcutaneous xenograft model of HCC was created in nude mice. HCC tissues and cells exhibited elevated level of miR-224-5p, while COLEC10 was lower. Overexpression miR-224-5p enhanced HCC cells proliferation, migration, invasion, EMT and inflammatory response, while suppressed apoptosis. Moreover, miR-224-5p targeted the expression of COLEC10 negatively. COLEC10 silenced could offset the suppression of HCC advancement induced by silenced miR-224-5p. While LYC down regulated miR-224-5p level and inhibited the HCC malignant progression. In conclusion, LYC can down regulate the levels of miR-224-5p, upregulate the levels of COLEC10 and thus inhibit the malignant progression of HCC.

This retrospective analysis aimed to evaluate the potential benefits of integrating transdermal acupoint therapy with the tonifying spleen and kidney method alongside growth hormone (GH) treatment for pediatric patients suffering from growth hormone deficiency (GHD). Clinical data of 115 pediatric patients with GHD were retrospectively analyzed. Patients were categorized into two distinct groups for the analysis: The conventional GH treatment group (n=62) and the combined group of acupoint transdermal therapy alongside GH treatment (n=53). Baseline characteristics, hormone levels, bone mineral density (BMD), physical growth parameters and adverse events were compared. The baseline characteristics of the two groups were well-matched. After one year of treatment, the combined group showed significantly lower levels of insulin-like growth factor-1 (P<0.001), testosterone (P<0.001), estrogen (P<0.001), thyroid-stimulating hormone (P<0.001), insulin-like growth factor binding protein-3 (P=0.009) and free thyroxine (P<0.001) compared to the conventional group. The transdermal treatment group demonstrated significantly higher BMD at multiple sites (P<0.05) and improved physical growth parameters (P<0.05) compared to the conventional group. Furthermore, the transdermal treatment was not linked to a higher occurrence of adverse incidents and showed significant correlations with various growth and development indexes (P<0.05). Combined therapy showed promising effects on endocrine function and physical growth.

Uncertainty in pharmaceutical manufacturing and real-world utility can lead to anxiety, while predictabilitysuch as meeting targets or passing inspections-instills confidence and ensures quality. A systems approach infused with design thinking is vital for accurately, precisely and consistently achieving the correct targets and evidencing success. This approach must address real-world needs, expectations and unadulterated communication of documented evidence of consistent quality. Cultivating higher consciousness, or qualia, is essential but challenging. As the world appears to spiral into chaos, how we tackle this challenge will determine whether we face a dystopian future or true enlightenment. This article explains why transforming the past is necessary and how to do so in a way that presents new, meaningful options for an enlightened future.