Exploring chemical space, scaffold diversity, and activity landscape of spleen tyrosine kinase active inhibitors.

This study aims to comprehensively characterize 576 inhibitors targeting Spleen Tyrosine Kinase (SYK), a non-receptor tyrosine kinase primarily found in haematopoietic cells, with significant relevance to B-cell receptor function. The objective is to gain insights into the structural requirements essential for potent activity, with implications for various therapeutic applications. Through chemoinformatic analyses, we focus on exploring the chemical space, scaffold diversity, and structure-activity relationships (SAR). By leveraging ECFP4 and MACCS fingerprints, we elucidate the relationship between chemical compounds and visualize the network using RDKit and NetworkX platforms. Additionally, compound clustering and visualization of the associated chemical space aid in understanding overall diversity. The outcomes include identifying consensus diversity patterns to assess global chemical space diversity. Furthermore, incorporating pairwise activity differences enhances the activity landscape visualization, revealing heterogeneous SAR patterns. The dataset analysed in this work has three activity cliff generators, CHEMBL3415598, CHEMBL4780257, and CHEMBL3265037, compounds with high affinity to SYK are very similar to compounds analogues with reasonable potency differences. Overall, this study provides a critical analysis of SYK inhibitors, uncovering potential scaffolds and chemical moieties crucial for their activity, thereby advancing the understanding of their therapeutic potential.

Development and rigorous validation of antimalarial predictive models using machine learning approaches.

The large collection of known and experimentally verified compounds from the ChEMBL database was used to build different classification models for predicting the antimalarial activity against Plasmodium falciparum. Four different machine learning methods, namely the support vector machine (SVM), random forest (RF), k-nearest neighbour (kNN) and XGBoost have been used for the development of models using the diverse antimalarial dataset from ChEMBL. A well-established feature selection framework was used to select the best subset from a larger pool of descriptors. Performance of the models was rigorously evaluated by evaluation of the applicability domain, Y-scrambling and AUC-ROC curve. Additionally, the predictive power of the models was also assessed using probability calibration and predictiveness curves. SVM and XGBoost showed the best performances, yielding an accuracy of ~85% on the independent test set. In term of probability prediction, SVM and XGBoost were well calibrated. Total gain (TG) from the predictiveness curve was more related to SVM (TG = 0.67) and XGBoost (TG = 0.75). These models also predict the high-affinity compounds from PubChem antimalarial bioassay (as external validation) with a high probability score. Our findings suggest that the selected models are robust and can be potentially useful for facilitating the discovery of antimalarial agents.

Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation.

OBJECTIVE: The objective of study was to develop an accurate and reproducible HPLC method for determination of piracetam in human plasma and to evaluate pharmacokinetic parameters of 800 mg piracetam. METHODS: A simple, rapid, accurate, precise and sensitive high pressure liquid chromatography method has been developed and subsequently validated for determination of piracetam. This study represents the results of a randomized, single-dose and single-period in 18 healthy male volunteers to assess pharmacokinetic parameters of 800 mg piracetam tablets. Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The data was analyzed by using Kinetica® version 4.4 according to non-compartment model of pharmacokinetic analysis and after comparison with previous studies, no significant differences were found in present study of tested product. RESULTS: The major pharmacokinetic parameters for piracetam were as follows: t1/2 was (4.40 ± 0.179) h; Tmax value was (2.33 ± 0.105) h; Cmax was (14.53 ± 0.282) µg/mL; the AUC(0-∞) was (59.19 ± 4.402) µg · h/mL. AUMC(0-∞) was (367.23 ± 38.96) µg. (h)(2)/mL; Ke was (0.16 ± 0.006) h; MRT was (5.80 ± 0.227) h; Vd was (96.36 ± 8.917 L). CONCLUSIONS: A rapid, accurate and precise high pressure liquid chromatography method was developed and validated before the study. It is concluded that this method is very useful for the analysis of pharmacokinetic parameters, in human plasma and assured the safety and efficacy of piracetam, can be effectively used in medical practice.

Hypercalcemic crisis due to primary hyperparathyroidism in systemic lupus erythematosus (SLE).

Severe hypercalcemia is often caused by primary hyperparathyroidism (PHP), which is not commonly seen in patients with systemic lupus erythematosus (SLE). In this case report an adolescent girl with a history of SLE develops mild hypercalcemia secondary to unrecognized PHP that leads to a hypercalcemic crisis with a prolonged recovery. Therefore, early diagnostic evaluation of persistent hypercalcemia in patients with SLE is important for detection and appropriate treatment of PHP to avoid a hypercalcemic crisis and associated prolonged morbidity.

Comparative analysis of knowledge, attitudes and perceptions about induced abortions among medical and non-medical students of Karachi.

OBJECTIVE: To determine the knowledge, attitudes and perceptions regarding induced abortions among university students of Karachi and compare these aspects among medical and non-medical students. STUDY DESIGN: Cross sectional opinion survey. METHODS: The study is a cross sectional opinion survey of medical and non-medical students from four educational institutions of Karachi using a pretested questionnaire. RESULTS: Of the 381 students interviewed, 201 were medical and 180 were non-medical. More medical students were aware of the correct definition of induced abortion. An encouraging finding was the awareness of our study population about the only legally acceptable circumstance for induced abortion in Pakistan, that is, if conceptus is a risk to maternal health (p<0.001). More medical students cited complications that were technical like uterine perforation (p<0.001), cervical trauma (p<0.001), DIC (p<0.001), and sepsis (p<0.001). More medical students thought induced abortion to be a health issue (p=0.001) as compared to non-medical students. Most of the medical students felt the need to modify Pakistan's law regarding abortion (p=0.008) especially for fetal anomalies (13.9%) and rape (7%). CONCLUSION: Though medical students were more knowledgeable about induced abortions as compared to the non-medical population, there is a need to improve awareness regarding induced and unsafe abortions and their consequences.

Disease pattern and fatality among patients treated at DHQ Hospital, Faisalabad.

A pilot study was undertaken to assess the pattern of diseases, fatality and some other ratios among the patients treated at District Headquarters Hospital, Faisalabad during 1984. Out of 4,506 in-patients, maximum admissions 1,196 (26.54%) were of gastrointestinal diseases followed by 795 (17.64%) cases of injuries. Overall fatality was found to be 6.35%. The highest case fatality was found in the infectious diseases group, while maximum of the total deaths (20.98%) occurred due to injuries. Consistency in provisional and final diagnosis was found in 86.20% of total cases. The annual turnover was 41 patients per bed per year.

Acute leukaemia in children--French-American-British (FAB) classification and its relation to clinical features.

A retrospective study of 45 patients of acute leukaemia in children (15 years age), in relation to FAB classification, is presented. Acute lymphoblastic leukaemias (ALL) were commoner than acute myeloid leukaemias (AML), with an ALL:AML ratio of 4.63:1. Amongst ALL, L1 was the most frequent type (59%), followed by L2 (35%) and L3 (5.4%), respectively. FAB types M2, M3, M4 and M5 were diagnosed in 2 patients each. An analysis of clinical features in relation to FAB classification is also presented.