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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.
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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.
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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.
