The population pharmacokinetics of R- and S-warfarin: effect of genetic and clinical factors

BACKGROUND

Warfarin is a drug with a narrow therapeutic index and large interindividual variability in daily dosing requirements. Patients commencing warfarin treatment are at risk of bleeding due to excessive anticoagulation caused by overdosing. The interindividual variability in dose requirements is influenced by a number of factors, including polymorphisms in genes mediating warfarin pharmacology, co-medication, age, sex, body size and diet.

AIMS

To develop population pharmacokinetic models of both R- and S-warfarin using clinical and genetic factors and to identify the covariates which influence the interindividual variability in the pharmacokinetic parameters of clearance and volume of distribution in patients on long-term warfarin therapy.

METHODS

Patients commencing warfarin therapy were followed up for 26 weeks. Plasma warfarin enantiomer concentrations were determined in 306 patients for S-warfarin and in 309 patients for R-warfarin at 1, 8 and 26 weeks. Patients were also genotyped for CYP2C9 variants (CYP2C9*1,*2 and *3), two single-nucleotide polymorphisms (SNPs) in CYP1A2, one SNP in CYP3A4 and six SNPs in CYP2C19. A base pharmacokinetic model was developed using NONMEM software to determine the warfarin clearance and volume of distribution. The model was extended to include covariates that influenced the between-subject variability.

RESULTS

Bodyweight, age, sex and CYP2C9 genotype significantly influenced S-warfarin clearance. The S-warfarin clearance was estimated to be 0.144 l h⁻¹ (95% confidence interval 0.131, 0.157) in a 70 kg woman aged 69.8 years with the wild-type CYP2C9 genotype, and the volume of distribution was 16.6 l (95% confidence interval 13.5, 19.7). Bodyweight and age, along with the SNPs rs3814637 (in CYP2C19) and rs2242480 (in CYP3A4), significantly influenced R-warfarin clearance. The R-warfarin clearance was estimated to be 0.125 l h⁻¹ (95% confidence interval 0.115, 0.135) in a 70 kg individual aged 69.8 years with the wild-type CYP2C19 and CYP3A4 genotypes, and the volume of distribution was 10.9 l (95% confidence interval 8.63, 13.2).

CONCLUSIONS

Our analysis, based on exposure rather than dose, provides quantitative estimates of the clinical and genetic factors impacting on the clearance of both the S- and R-enantiomers of warfarin, which can be used in developing improved dosing algorithms.     

Effects of tight versus non tight control of metabolic acidosis on early renal function after kidney transplantation

Background

Recently, several studies have been conducted to determine the optimal strategy for intra-operative fluid replacement therapy in renal transplantation surgery. Since infusion of sodium bicarbonate as a buffer seems to be safer than other buffer compounds (lactate, gluconate, acetate)that indirectly convert into it within the liver, We hypothesized tight control of metabolic acidosis by infusion of sodium bicarbonate may improve early post-operative renal function in renal transplant recipients.

Methods

120 patients were randomly divided into two equal groups. In group A, bicarbonate was infused intra-operatively according to Base Excess (BE) measurements to achieve the normal values of BE (−5 to +5 mEq/L). In group B, infusion of bicarbonate was allowed only in case of severe metabolic acidosis (BE ≤ −15 mEq/L or bicarbonate ≤ 10 mEq/L or PH ≤ 7.15). Minute ventilation was adjusted to keep PaCO₂ within the normal range. Primary end-point was sampling of serum creatinine level in first, second, third and seventh post-operative days for statistical comparison between groups. Secondary objectives were comparison of cumulative urine volumes in the first 24 h of post-operative period and serum BUN levels which were obtained in first, second, third and seventh post-operative days.

Results

In group A, all of consecutive serum creatinine levels were significantly lower in comparison with group B. With regard to secondary outcomes, no significant difference between groups was observed.

Conclusion

Intra-operative tight control of metabolic acidosis by infusion of Sodium Bicarbonate in renal transplant recipients may improve early post-operative renal function.     

The prevalence of obesity and its related risk factor in the north of iran in 2006

Background: The main objective of this study was to evaluate the prevalence of the obesity and the related risk factors in the north of Iran. Methods: This was a population-based cross-sectional study that enrolled 2495 subjects (1247 males and 1248 females) using stratified cluster sampling. Interviewers recorded the data using a multidimensional questionnaire including anthropometric indexes. Body mass index equal to or greater than 25 was considered as overweight and that of 30 and 40 as obese and pathologic obese respectively. SPSS 16.0 software was used for statistical data analysis. Results: Mean age of the subjects was 39.2 [95% CI: 38.6, 39.8] yr. Mean body mass index was 25.3 [95% CI: 25.0, 25.6] kg/m(2) for men and 27.5 [95% CI: 27.2, 27.9] kg/m2 for women. The prevalence rates of overweight, obesity and pathologic obesity were 29.9% (745/2495), 22.5% (561/2495) and 1.8% (44/2495) respectively. The prevalence of obesity was higher in urban residents than rural ones, 27.3% versus 18.9% respectively (P<0.001). The prevalence rates of obesity and pathologic obesity were much higher in women than men were, 30.3% versus 15.4% and 3.0% versus 0.6% respectively (P=0.001). The odds ratio estimate was 1.68 [95% CI: 1.40, 2.02] for urban area compared to rural area; 2.60 [95% CI: 2.14, 3.15] for females compared to males; 5.95 [95% CI: 3.54, 9.99] for married people compared to single people; 1.89 [95% CI: 1.44, 2.84] for age group of 55-65 years compared to age group of 15-24 years; 1.76 [95% CI: 1.17, 2.64] for illiterate people compared to those who had academic education; 1.98 [95% CI: 1.13, 2.49] for poor people compared to people with high economic level. Conclusion: The prevalence of obesity and overweight is very high in the north of Iran, hence is a signal of serious health problem, and should be the focus of special attention.     

The immunological benefit of higher dose N-acetyl cysteine following mechanical ventilation in critically ill patients

Background

Sepsis complication is a major cause of death in multiple trauma critically ill patients. Defensin (cysteine rich anti-microbial peptides), as an important component of immune system, might play an important role in this process. There is also rising data on immunological effects of N-acetyl-cysteine (NAC), a commonly used anti-oxidant in oxidative stress conditions and glutathione (GSH) deficiencies. The aim of the present study was to evaluate the potential beneficial effects of NAC administration on multiple trauma patients with sepsis.

Methods

In a prospective, randomized controlled study, 44 multiple trauma critically ill patients who were mechanically ventilated and met the criteria of sepsis and admitted to the intensive care unit (ICU) were randomized into two groups . Control group received all standard ICU therapies and NAC group received intravenous NAC 3 gr every 6 hours for 72 hours in addition to standard therapies. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores, length of ICU stay, ICU mortality were recorded. Levels of serum Immunoglobulin M (IgM), Human β-Defensin 2 (HβD2) and GSH were assessed at baseline and 24, 72, 120 hours after intervention.

Results

During a period of 13-month screening, 44 patients underwent randomization but 5 patients had to be excluded. 21 patients in NAC group and 18 patients in control group completed the study. For both groups the length of ICU stay, SOFA score and systemic oxygenation were similar. Mortality rate (40% vs. 22% respectively, p = 0.209) and ventilator days (Mean ± SD 19.82 ± 19.55 days vs. 13.82 ± 11.89 days respectively, p = 0.266) were slightly higher for NAC group. IgM and GSH levels were similar between two groups (p = 0.325, 0.125 respectively), HβD2 levels were higher for NAC group (at day 3).

Conclusion

High dose of NAC administration not only did not improve patients’ outcome, but also raised the risk of inflammation and was associated with increased serum creatinine.     

Seroprevalence of toxoplasmosis in HIV(+)/AIDS patients in Iran

Toxoplasma gondii has arisen as an important opportunistic agent especially in the central nervous system and in advanced HIV disease can cause significant morbidity and mortality. This study was carried out to determine the seroprevalence of toxoplasmosis among HIV-positive patients in Iran. Blood samples were collected from 201 HIV-positive patients and anti-toxoplasma antibodies were detected by using conventional ELISA. An antibody titer of >3 IU/ml was considered positive. The majority of studied patients were male (male to female ratio: 5 to 1) with the mean age of 36 ± 1 yrs. The seroprevalence of toxoplasmosis in HIV-positive patients was 49.75%. The mean CD4 count in HIV patients with positive toxoplasma serology was 332.5 ± 22.4 cells/μl. Only 1% of the patients had IgM anti-toxoplasma antibodies and 10% of the patients had clinical toxoplasma encephalitis. The mean CD4 count in this group was 66.4 ± 15.5 cells/μl and there was a significant association between CD4 count and rate of toxoplasma encephalitis (P<0.001). Previous reports suggested that toxoplasma encephalitis could be prevented by appropriate chemoprophylaxis. In view of the relatively high prevalence of toxoplasma infection found among the HIV-infected patients in our study, we suggest that routine screening for toxoplasma should be undertaken for all HIV-infected patients in Iran.     

Association of educational status with cardiovascular disease: Teheran Lipid and Glucose Study

Objective  

The aim of this study was to evaluate the associations between educational level and cardiovascular disease (CVD) in an older Iranian population.     

Applications,functions, and accuracy of artificial intelligence in restorative dentistry: A literature review

Objective

The applications of artificial intelligence (AI) are increasing in restorative dentistry; however, the AI performance is unclear for dental professionals. The purpose of this narrative review was to evaluate the applications, functions, and accuracy of AI in diverse aspects of restorative dentistry including caries detection, tooth preparation margin detection, tooth restoration design, metal structure casting, dental restoration/implant detection, removable partial denture design, and tooth shade determination.

Overview

An electronic search was performed on Medline/PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar databases. English-language articles, published from January 1, 2000, to March 1, 2022, relevant to the aforementioned aspects were selected using the key terms of artificial intelligence, machine learning, deep learning, artificial neural networks, convolutional neural networks, clustering, soft computing, automated planning, computational learning, computer vision, and automated reasoning as inclusion criteria. A manual search was also performed. Therefore, 157 articles were included, reviewed, and discussed.

Conclusions

Based on the current literature, the AI models have shown promising performance in the mentioned aspects when being compared with traditional approaches in terms of accuracy; however, as these models are still in development, more studies are required to validate their accuracy and apply them to routine clinical practice. Clinical Significance: AI with its specific functions has shown successful applications with acceptable accuracy in diverse aspects of restorative dentistry. The understanding of these functions may lead to novel applications with optimal accuracy for AI in restorative dentistry.     

Gene regulation of aldose-, aldehyde- and a renal specific oxido reductase (RSOR) in the pathobiology of diabetes mellitus

Aldose-, aldehyde and renal specific oxido reductase (RSOR) belong to the family of aldo-keto reductases (AKRs). They are monomeric (alpha/beta)8-barrel proteins with a molecular weight ranging from 30 to 40 kDa, and at present include more than 60 members. Except for RSOR, they are expressed in a wide variety of animal and plant species and in various tissues. They catalyze NADPH-dependent reduction of various aliphatic and aromatic aldehyde and ketones. During the past three decades aldehyde reductase (AKR1A) and aldose reductase (AKR1B) have been extensively investigated, and the gene regulation of AKR1B has been noted to be heavily influenced by hyperglycemic state and high glucose ambience in various culture systems. AKR1B catalyzes the conversion of glucose to sorbitol in concert with a coenzyme, NADPH. The newly discovered RSOR has certain structural and functional similarities to AKR1B and seems to be relevant to the renal complications of diabetes mellitus. Like other AKRs, it has a NADPH binding motif, however, it is located at the N-terminus and it probably undergoes N-linked glycosylation in order to achieve functional substrate specificity. Besides the AKR3 motif, it has very little nucleotide or protein sequence homology with other members of the AKR family. Nevertheless, gene regulation of RSOR, like AKR1B, is heavily modulated by carbonyl, oxidative and osmotic stresses, and thus it is anticipated that its discovery would lead to the development of new inhibitors as well as gene therapy targets to alleviate the complications of diabetes mellitus in the future.     

Adult height and risk of coronary heart disease: Tehran Lipid and Glucose Study

Background

We assessed the relationship between height and coronary heart disease (CHD) in an urban population of Tehran.

Methods

4110 participants of the Tehran Lipid and Glucose Study who were 40 years of age or older (1880 men and 2230 women; mean age, 55.1 and 53.0 years, respectively) and free of CHD at baseline were followed for a mean of 9.1 years. We used Cox proportional hazards regression to evaluate the risk of a first CHD event across height tertiles.

Results

First CHD events occurred in 239 men and 172 women. The estimated crude HR (95% CI) for CHD events associated with an increment of 1 SD in height was 0.96 (0.28–3.33) in men and 0.84 (0.72–0.97) in women. After adjustment for age, the associations were no longer present. Further adjustment for other confounders had little impact on the results: the HR (95% CI) associated with an increase of 1 SD in height was 1.02 (0.87–1.20) in men and 0.82 (0.66–1.02) in women.

Conclusions

After adjustment for age, height was not associated with CHD incidence in men or women.Key words: height, coronary heart disease, cohort study     

Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot,Randomized, Double‐Blinded,Placebo‐Controlled Clinical Trial

Despite several introduced preventive modalities, cisplatin nephrotoxicity remains a clinical problem. Some in vitro and in vivo studies have addressed the protective effects of silymarin against cisplatin nephrotoxicity. This study evaluated the effects of silymarin administration on cisplatin nephrotoxicity as the first human study. During this pilot, randomized, double‐blinded, placebo‐controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting 24–48 h before the initiation of cisplatin infusion and continuing to the end of three 21‐day cisplatin‐containing chemotherapy courses on cisplatin‐induced renal electrolytes wasting and kidney function were assessed. Cisplatin‐associated acute kidney injury (AKI) occurred in 8% of the patients. Urine neutrophil gelatinase‐associated lipocalin to urine creatinine ratio (NGAL/Cr) and urinary magnesium and potassium wasting increased significantly after cisplatin infusion in both groups. Significant positive correlation was found between cumulative dose of cisplatin and urine NGAL/Cr after three courses of cisplatin infusion. Incidence of AKI and the magnitude of urinary magnesium and potassium wasting did not differ between silymarin and placebo groups. No adverse reaction was reported by silymarin administration. Prophylactic administration of conventional form of silymarin tablets could not prevent cisplatin‐induced urine electrolyte wasting or renal function impairment. Copyright © 2015 John Wiley & Sons, Ltd.