Utilization of Pharmacokinetic/Pharmacodynamic Modeling in Pharmacoepidemiological Studies:A Systematic Review on Antiarrhythmic and Glucose-Lowering Medicines

Introduction: In human pharmacology, there are two important scientific branches: clinical pharmacology and pharmacoepidemiology. Pharmacokinetic/pharmacodynamic (PK/PD) modeling is important in preclinical studies and randomized control trials. However, it is rarely used in pharmacoepidemiological studies on the effectiveness and medication safety where the target population is heterogeneous and followed for longer periods. The objective of this literature review was to investigate how far PK/PD modeling is utilized in observational studies on glucose-lowering and antiarrhythmic drugs. Method: A systematic literature search of MEDLINE, Embase, and Web of Science was conducted from January 2010 to 21 February 2020. To calculate the utilization of PK/PD modeling in observational studies, we followed two search strategies. In the first strategy, we screened a 1% random set from 95,672 studies on glucose-lowering and antiarrhythmic drugs on inclusion criteria. In the second strategy, we evaluated the percentage of studies in which PK/PD modeling techniques were utilized. Subsequently, we divided the total number of included studies in the second search strategy by the total number of eligible studies in the first search strategy. Results: The comprehensive search of databases and the manual search of included references yielded a total of 29 studies included in the qualitative synthesis of our systematic review. Nearly all 29 studies had utilized a PK model, whereas only two studies developed a PD model to evaluate the effectiveness of medications. In total, 16 out of 29 studies (55.1%) used a PK/PD model in the observational setting to study effect modification. The utilization of PK/PD modeling in observational studies was calculated as 0.42%. Conclusion: PK/PD modeling techniques were substantially underutilized in observational studies of antiarrhythmic and glucose-lowering drugs during the past decade

Statin Use and Coronary Artery Calcification: a Systematic Review and Meta-analysis of Observational Studies and Randomized Controlled Trials

Purpose of Review: This review aimed to determine the association between statin use and coronary artery calcification (CAC), as detected by computed tomography in the general population, in previously published observational studies (OSs) and randomized controlled trials (RCTs). Recent Findings: A systematic search until February 2022 identified 41 relevant studies, comprising 29 OSs and 12 RCTs. We employed six meta-analysis models, stratifying studies based on design and effect metrics. For cohort studies, the pooled β of the association with CAC quantified by the Agatston score was 0.11 (95% CI = 0.05; 0.16), with an average follow-up time per person (AFTP) of 3.68 years. Cross-sectional studies indicated a pooled odds ratio of 2.11 (95% CI = 1.61; 2.78) for the presence of CAC. In RCTs, the pooled standardized mean differences (SMDs) for CAC, quantified by Agatston score or volume, over and AFTP of 1.25 years were not statistically significant (SMD = − 0.06, 95% CI = − 0.19; 0.06 and SMD = 0.26, 95% CI = − 0.66; 1.19), but significantly different (p-value = 0.04). Meta-regression and subgroup analyses did not show any significant differences in pooled estimates across covariates. Summary: The effect of statins on CAC differs across study designs. OSs demonstrate associations between statin use and higher CAC scores and presence while being prone to confounding by indication. Effects from RCTs do not reach statistical significance and vary depending on the quantification method, hampering drawing conclusions. Further investigations are required to address the limitations inherent in each approach

Serum sclerostin is associated with recurrent kidney stone formation independent of hypercalciuria

ABSTRACT Background Kidney stones are frequent in industrialized countries with a lifetime risk of 10 to 15%. A high percentage of individuals experience recurrence. Calcium-containing stones account for more than 80% of kidney stones. Diet, environmental factors, behavior, and genetic variants contribute to the development of kidney stones. Osteocytes excrete the 21 kDa glycoprotein sclerostin, which inhibits bone formation by osteoblasts. Animal data suggests that sclerostin might directly or indirectly regulate calcium excretion via the kidney. As hypercalciuria is one of the most relevant risk factors for kidney stones, sclerostin might possess pathogenic relevance in nephrolithiasis. Methods We performed a prospective cross-sectional observational controlled study in 150 recurrent kidney stone formers (rKSF) to analyse the association of sclerostin with known stone risk factors and important modulators of calcium-phosphate metabolism. Serum sclerostin levels were determined at the first visit. As controls, we used 388 non-stone formers from a large Swiss epidemiological cohort. Results Sclerostin was mildly increased in rKSF in comparison to controls. This finding was more pronounced in women compared to men. Logistic regression indicated an association of serum sclerostin with rKSF status. In hypercalciuric individuals, sclerostin levels were not different from normocalciuric patients. In Spearman correlation analysis we found a positive correlation between sclerostin, age, and BMI and a negative correlation with eGFR. There was a weak correlation with iPTH and intact FGF 23. In contrast, serum sclerostin levels were not associated with 25-OH Vitamin D3, 1,25-dihydroxy-Vitamin D3, urinary calcium and phosphate or other urinary lithogenic risk factors. Conclusion This is the first prospective controlled study investigating serum sclerostin in rKSF. Sclerostin levels were increased in rKSF independent of hypercalciuria and significantly associated with the status as rKSF. It appears that mechanisms other than hypercalciuria may be involved and thus further studies are required to elucidate underlying pathways

The Effect of Plantago major Hydroalcoholic Extract on the Healing of Diabetic Foot and Pressure Ulcers: A Randomized Open-Label Controlled Clinical Trial

Aims: Diabetic foot ulcer (DFU) and pressure ulcer (PU) both are common types of ulcers worldwide. The wound healing effect of Plantago major leaves has been shown in a few animal studies. This study aimed to evaluate the clinical efficacy of P. major hydroalcoholic extract on DFU and PU healing.   Methods: In this clinical trial, patients with DFU or PU who met the inclusion criteria were randomly assigned to drug (P. major) or control groups. For patients in the drug group, Plantago extract 10% topical gel was applied on the wound once daily concurrent with dressing and routine wound care for two weeks, while for the control group, an appropriate novel dressing was used along with routine wound care for the same duration. The percentage of wound size reduction at the end of the seventh and 14th days of intervention was recorded and compared between the groups.   Results: Fifty and 44 patients in drug and control groups, respectively, completed the interventions. Plantago extract gel significantly resulted in more reduction in the wound size compared to control at the end of the first (64.90 ± 29.75% vs. 33.11 ± 26.55%; P < 0.001) and second week (86.85 ± 24.34% vs. 52.87 ± 32.41%; P < 0.001). Furthermore, the number of patients with complete wound healing in the drug group (n = 32, 64%) was significantly more than the control group (n = 9, 20.45%; OR: 3.129, 95% CI: 1.685-5.809, P < 0.001).  Conclusion: The use of 10% topical gel of P. major leaf extract results in the acceleration of DFU and PU healing. Key points: Application of P. major topical gel results in the acceleration of diabetic foot ulcer and pressure ulcer healing. - P. major extract helps reducing the wound's erythema. - P. major leaf extract assists decreasing the wound size. - The number of patients completing wound healing process is higher among whom undergoing P. major dressing

Pediatric toxicoepidemiology of tramadol intoxication in Iran: a\ua05-year cross-sectional study

Objective: We aimed to find the toxicoepidemiological indicators of tramadol poisoning in children and also the relationship of these indicators (such as demographic characteristics, and referral time) with the final therapeutic outcome. Methods: In this cross-sectional study with retrospective data collection, we included the records for all the patients under 18 that have been admitted due to tramadol poisoning between 2010 and 2015 to Noor and Ali-Asghar (PBUH) University hospital which serves as the referral medical center for acute poisonings management in the central part of Iran and is located in Isfahan. Demographic characteristics, ingested dose, dosage forms, clinical manifestations, coingested drugs, and the outcome of treatment for all pediatric patients were documented and descriptively analyzed. Findings: Demographic and clinical data of a total of 189 patients including 101 male (53.4%) with a mean age of 16.66 +/- 2.64 years were abstracted and included in this study. The average time between tramadol ingestion and hospital admission was 3.39 +/- 3.23 h. Mean duration of hospitalization was 12.3 +/- 10.7 h. In all cases, the route of drug exposure was oral, and the most common form of drug dosage form was 100 mg tablets (n = 122) proceeded by 200 mg tablets (n = 32). The mean estimated dose of ingested tramadol was 1126 +/- 1061 mg (median, 900 range, 50-7000 mg). 43.9% of the poisoned patients were high school students, and 23.3% had a high school diploma. Intentional intoxications were reported in 93.1% cases and 42.9% had coingestions. Activated charcoal (87.3%), gastric lavage (59.3%), oxygen therapy with mask (46.6%), naloxone (11.6%), anticonvulsants (13.2%), and intubation and ventilation (5.3%) were done as first-line therapeutic measures. Conclusion: Our results suggest that the trend of acute tramadol poisoning among children is decreasing, mostly accidental in adolescents and commonly intentional among young children. Proper education to improve emotional intelligence for young adults and to keep drugs out of reach of the children and safer packaging is recommended to reduce tramadol poisoning incidence in the pediatric population

Clinical Impact and Mechanisms of Nonatherosclerotic Vascular Aging:The New Kid to Be Blocked

Ischemic cardiovascular disease and stroke remain the leading cause of global morbidity and mortality. During aging, protective mechanisms in the body gradually deteriorate, resulting in functional, structural, and morphologic changes that affect the vascular system. Because atherosclerotic plaques are not always present along with these alterations, we refer to this kind of vascular aging as nonatherosclerotic vascular aging (NAVA). To maintain proper vascular function during NAVA, it is important to preserve intracellular signalling, prevent inflammation, and block the development of senescent cells. Pharmacologic interventions targeting these components are potential therapeutic approaches for NAVA, with a particular emphasis on inflammation and senescence. This review provides an overview of the pathophysiology of vascular aging and explores potential pharmacotherapies that can improve the function of aged vasculature, focusing on NAVA.</p