The Bronchodilator Potential of Astragalus sarcocolla: An in vitro Experiment.

OBJECTIVE: To evaluate the bronchodilatory mechanism of Astragalus sarcocolla (ASE) extract on tracheal smooth muscles of rabbits. STUDY DESIGN: In-vitro experimental study. Place and Duration of the Study: The animal house of CMH Lahore Medical College, Lahore, and Institute of Dentistry, NUMS, from October 2022 to May 2023. METHODOLOGY: Six rabbits were randomly divided into four groups. After euthanising the rabbit, the trachea was carefully dissected out and stabilised in Kreb's Henseleit solution for 30 minutes and then, stimulated by acetylcholine (Ach) 1µm, under mimicked physiological conditions. Group I served as the control group with tracheal smooth muscles stabilised with 1g tension. In Group II (positive control), tracheal smooth muscles were stimulated by potassium chloride (KCl) (80 mM and 25 mM, respectively) to get maximum tracheal smooth muscle contractions. Later, the tissue was exposed to theophylline with three molar concentrations 0.2, 0.4, 0.6, and 0.8 mM, and cumulative dose response curves were formed. In Group III (ASE group), tracheal smooth muscles were stimulated by KCl (80 mM and 25 mM) and was exposed to increasing concentration of ASE. In group IV, tissue was stimulated by KCl (25 mM) and glibenclamide (3 µM), later exposed to increasing concentration of ASE to confirm the bronchodilatory mechanism. The change in isometric contraction of the tissue was recorded using the force displacement transducer connected to a PowerLab data acquisition system. Concentration response curves were drawn, and median effective concentrations (EC50 values) and percentage inhibition were calculated. Non-linear regression was applied for the analysis of the concentration-response curves. RESULTS: ASE inhibited the KCl-induced low potassium (25 mM) contractions (EC50 = 0.38 mg/ml, 95% CI: 0.04 - 0.38, n = 6). It only partially inhibited the high potassium-induced contractions in tracheal smooth muscles. Pretreatment with glibenclamide showed a rightward shift of the dose-response curve. Theophylline and ASE significantly reduced the low K+ induced smooth muscle contractions in comparison to the control group (p <0.001, each). CONCLUSION: Astragalus sarcocolla extract produced bronchodilator effects through the activation of ATP sensitive potassium channels in isolated rabbit trachea. KEY WORDS: Astragalus sarcocolla, Bronchodilators, ATP-sensitive potassium channels, Effective concentration 50, Concentration response curves.

Comparative pharmacokinetics of valproic acid among Pakistani and South Korean patients: A population pharmacokinetic study.

PURPOSE: The pharmacokinetics of valproic acid have been evaluated in a variety of populations however, the comparison in two different populations was yet to be reported. This study is aimed to compare the pharmacokinetics of valproic acid in Pakistani and South Korean patients. METHOD: The therapeutic drug monitoring (TDM) data of valproic acid from 92 Pakistani patients with 218 samples was combined with the data of 99 South Korean patients with 335 samples in order to form a pooled dataset of 191 patients with 553 samples. Population pharmacokinetic model was developed on NONMEM® software by using first order conditional estimation method for estimation of pharmacokinetic parameters. The influence of different covariates including ethnicity was evaluated the stepwise covariate modelling. The final model was evaluated for predictive performance and robustness by using goodness of fit plots and bootstrap analysis respectively. RESULTS: The data was better described by one compartment model with first order elimination. The value for clearance (CL) of valproic in pooled data was 0.931 L/h with 43.4% interindividual variability (IIV) while volume of distribution (Vd) was 16.6 L with 22.3% IIV. In covariate analysis, ethnicity and body weight were significant covariates for CL while body weight was also significant for Vd. CONCLUSION: A significant difference in CL of valproic acid among Pakistani and South Korean patients was observed. The model can be used for the dose tailoring of valproic acid based on ethnicity and body weight of Pakistani and South Korean patients.

Rasagiline Pharmacokinetics in CYP1A2 Variant Healthy Smokers & Non-smokers in Different Doses.

Objectives: Rasagiline, a drug for Parkinson's disease is metabolized by CYP1A2 enzyme. The objective of the study was to investigate the influence of cytochrome P450 1A2 variants and smoking status of healthy individuals on the pharmacokinetics of rasagiline. Methods: A comparative, open label, interventional, single oral dose, pharmacokinetic study was performed on 108 healthy volunteers in UHS & UVAS, Lahore. Data collection was initiated in June 2016 and ended in January 2018. It was divided in three phases with 1, 2 and 5mg of rasagiline given to a group of 36 volunteers in each phase. Volunteers were sub-divided into six groups of AA smokers, AA non-smokers, AC smokers, AC non-smokers, CC smokers & CC non-smokers on the basis of genotyping and smoking status. Serial blood sampling was performed at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8 & 12 hours after administration of rasagiline tablets. Plasma concentrations were determined using High Performance Liquid Chromatography (HPLC) method. Pharmacokinetic (PK) parameters were calculated using software (APO) pharmacological analysis. Results: Analysis of variance (ANOVA) showed significant difference between AA and CC groups. Multiple group comparison with post hoc Tukey's revealed that AA-smokers had significantly less tmax (p<0.001), t1/2 (p<0.012), AUC (p<0.008) and highest Cl (p<0.001) as compared to CC-smokers. The trend was same across all three doses. Conclusion: The study concludes that the systemic metabolism of rasagiline is significantly increased in CYP1A2*AA variants while smoking status did not show consistent difference in PK parameters.

Safety, effectiveness and hesitancy of COVID-19 vaccination in children: A cross-sectional study in Pakistan.

Background: The elevated risk of serious complications like myocarditis and pericarditis after COVID-19 vaccination, especially in adolescent has been reported in some instances that need to be tested in regional populations and different ethnicity groups. The purpose of the study was to evaluate the side effects, hesitancy, and effectiveness outcomes following COVID-19 vaccination among children in Pakistan. Methods: The study was planned using a cross-sectional design and data from Children and Adolescents (CA) was collected through a convenient sampling method using a validated questionnaire between February to July 2022. A total of 1,108 CA between the age of 12-18 years who received one or two doses of vaccine were selected and data were collected through direct interviews with respondents. Results: The results showed that among 99.8% of respondents who received the Pfizer COVID-19 vaccine, 72.3% of respondents were partially vaccinated (with one dose) while 27.7% were fully vaccinated (with two doses). COVID vaccination regime had a favorable safety profile in children as compared to adults. Vaccine hesitancy in children was reported to be 52.4% and the most common reasons for hesitance were the assumption that the vaccine is not safe (23.7%), the vaccine is not required (19.6%) and the vaccine is not effective (10.4%). The reported side effects were mainly mild (88.5%) followed by moderate (10.6%) and only 0.8% were of severe intensity. Post-vaccination local side effects of mild intensity were common with an onset of an average of 24 h (68%) and a duration of 2-3 days (60.6%). The reported side effects were significantly associated with gender (p = 0.00) while age had no significant effect on the occurrence of side effects. Overall, the vaccine was well tolerated by children and adolescents and was effective in preventing the reoccurrence of COVID-19 infection in 99.9% of participants. Conclusion: COVID-19 vaccine by Pfizer approved by the FDA for use in CA 12-18 years of age was well tolerated with a good safety profile and no serious adverse drug reactions were reported. The vaccine side effects were mild (88.5%) and lasted for an average of 2-3 days only (60.4%). The vaccine was effective in safeguarding Children against COVID-19 infection.

Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan.

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan. Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration-time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks. Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively. Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

Antihyperlipidaemic effects of Eugenia jambolana fruit in diet induced hyperlipidaemic rats.

OBJECTIVE: To evaluate the antihyperlipidaemic effects of Eugenia jambolana fruit pulp in diet induced hyperlipidaemic rats and to compare them with Simvastatin. METHODS: An experimental randomised control study was conducted on seventy five male albino rats, divided into five groups labelled A, B, C, D and E with fifteen rats in each group. Group A was kept as normal control, groups B, C, D and E were given hyperlipidaemic diet for six weeks. In group B no further intervention was done, group C and group D were given ethanolic extract of Eugenia Jambolana and Simvastatin respectively for eight weeks. Group E was given combination of both for same duration. Serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides were measured at zero, six and fourteen weeks. RESULTS: At fourteenth week significant reductions in total cholesterol, low density lipoprotein cholesterol and triglycerides and a rise in high density lipoprotein cholesterol was observed in interventional groups C, D and E as compared to experimental hyperlipidaemic control group B (p < 0.05). There was no significant difference at baseline (zero weeks) serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides of groups A, B, C, D & E; p > 0.24, p > 0.37, p > 0.89, p > 0.2, respectively. On sixth week, there was no significant difference between groups B, C, D and E (p > 0.05). However, 15 rats of group A had significant lower levels of cholesterol, high density lipoproteins, low density lipoproteins and triglycerides when compared to 60 rats of groups B, C, D and E (p < 0.05). CONCLUSION: In male albino rats ethanolic extract of Eugenia Jambolana fruit pulp was as effective as simvastatin in lowering serum total cholesterol, low density lipoprotein cholesterol and triglycerides and increasing high density lipoprotein cholesterol.

Comparison of simvastatin with Eugenia Jambolana fruit pulp in their effects on alanine transferase, aspartate aminotransferase and creatinine phosphokinase levels of hyperlipidaemic rats.

OBJECTIVES: To compare the effects of Eugenia Jambolana fruit extract with simvastatin on liver enzymes, aspartate aminotransferase (AST), alanine transferase (ALT) and muscle enzyme creatinine phosphokinase (CPK) in diet induced hyperlipidaemic rats. METHODS: An experimental randomized control study was conducted on seventy five male albino rats, divided into five groups labelled A, B, C, D and E with fifteen rats in each group. Group A was kept as normal control, groups B, C, D and E were given hyperlipidaemic diet for six weeks. In group B no further intervention was done, group C and group D were given ethanolic extract of Eugenia Jambolana and Simvastatin respectively for eight weeks. Group E was given combination of both for same duration. Serum Total Cholesterol (TC), Low density lipoprotein (LDL), High density lipoprotein (HDL), Triglycerides (TG), ALT. AST and CPK were measured at zero, six and fourteen weeks. RESULTS: At fourteenth week significant reductions in serum ALT , AST and CPK levels were observed in hyperlipidaemic group C as compared to other hyperlipidaemic groups B, D and E (p<0.05). Serum ALT level which is considered to be the most important parameter of hepatotoxicity returned to normal after 8 weeks in group C fed on Eugenia Jambolana fruit pulp only and the values were equal to control group A. There was no significant difference at baseline (zero weeks) serum TC, LDL, HDL, TG, ALT, AST and CPK of groups A, B, C, D and E; p>0.24, p>0.37, p>0.89, respectively. On sixth week, serum ALT, AST and CPK levels of hyperlipidaemic groups B,C,D and E were found to be significantly higher as compared to group A (p<0.05). CONCLUSION: Ethanolic extract of Eugenia Jambolana fruit caused a reduction in serum ALT, AST and CPK level in male albino rats when compared with simvastatin.