Drug metabolism and personalized therapy最新文献

Objectives: While the existing literature extensively covers the topic of tacrolimus variability, it remains crucial to gather data that are tailored to the Tunisian population. Our primary goal was to assess the variability in tacrolimus bioavailability using the Cp(0)/weight dosage ratio in Tunisian kidney transplant patients. We also aimed to determine the correlations between blood trough level (Cp(0)) and the area under the concentration-time curve (AUC0-12 h) in this cohort.

Methods: This retrospective study included patients treated with oral tacrolimus for the prevention of organ rejection between 2009 and 2023. The correlation between parameters was analyzed through a Pearson coefficient and a regression model. We assessed the inter- and intraindividual variability by calculating the coefficient of variation for patients with at least three samples.

Results: Analysis of 2,124 samples revealed a weak correlation (R=0.121) between Cp(0) and weight dosage. We found that 79.3 % of patients exhibited high variability in the Cp(0)/weight dosage ratio. A strong correlation (R=0.797) was found between Cp(0) and the AUC0-12 h. We also found that 47.6 % of patients showed high variability in the AUC0-12 h/Cp(0) ratio.

Conclusions: This study underscores the necessity for individualized therapeutic drug monitoring in Tunisian kidney transplant recipients due to the high variability in the Cp(0)/weight dosage ratio. The AUC0-12 h/Cp(0) ratio is proposed as a more consistent parameter for therapeutic drug monitoring, offering potential improvements in tacrolimus therapy management.

Objectives: Exercise capacity is decreased in diabetes mellitus due to impaired insulin sensitivity, endothelial dysfunction and mitochondrial dysfunction. The aim of the study was to evaluate the effect of metformin on exercise capacity in treatment naïve patients with type 2 diabetes mellitus.

Methods: Newly diagnosed type 2 diabetes mellitus patients were tested for baseline insulin resistance and exercise capacity, before starting on metformin. Exercise capacity was measured by incremental exercise testing in treadmill (ZAN 600 CPET system) using modified Bruce protocol at baseline, 6 weeks and 12 weeks following metformin therapy.

Results: A total of 33 treatment naïve type 2 diabetes patients were enrolled of which 19 patients completed the study. There was no significant change in any of the exercise capacity parameters at the end of 12 weeks of metformin. Nevertheless, there was a significant improvement in VO₂/kg among those with insulin resistance as compared to those without insulin resistance.

Conclusions: Metformin monotherapy did not produce any change in exercise capacity in treatment naïve type 2 diabetes patients. However, a significant fall in exercise capacity (VO₂/kg) was observed in patients without insulin resistance as compared to those with insulin resistance at the end of 12 weeks of metformin therapy.

The CYP2C19 enzyme is implicated in the metabolism of several clinically used drugs. Its phenotype is usually predicted by genotyping and indicates the expected enzymatic activity for each patient. However, with a few exceptions, CYP2C19 genotyping has not resulted in a reliable prediction of the metabolizer status, since most of the evidence currently available for this prediction comes from research into populations of predominantly European ancestry. Therefore, this review discusses the main factors that may alter the expected phenotype, as well as the urgent need to include ethnically diverse populations in further studies, so that, in the long term, it is possible to establish guidelines appropriate to these groups.

Objectives: Vernonia amygdalina Del. is a perennial tropical shrub from Asteraceae. The fresh leaf of V. amygdalina is consumed as a vegetable due to its medicinal and nutritional properties. The present study focused on the quantification of bioactive compounds, luteolin-7-O-glucoside, luteolin-7-O-glucuronide, and 1,5-O-dicaffeoylquinic acid from aqueous leaf extract of V. amygdalina. The study also aims to investigate the effects of the aqueous leaf extract of V. amygdalina on cytochrome P450 2C9 (CYP2C9), and cytochrome P450 3A4 (CYP3A4) in hepatic cells of control and diabetic rats.

Methods: The quantification of the bioactive compounds was conducted using ultra-high-performance liquid chromatography multiple reactions monitoring tandem mass spectrometry (UHPLC-MS/MS-MRM) technique. The effect of the extract on CYP2C9 and CYP3A4 activities was determined using a fluorometric screening kit according to the manufacturer's instructions.

Results: The three bioactive compounds were detected and quantified in the aqueous leaf extract. Results showed that the content of luteolin-7-O-glucuronide (47 μg/mg) was the highest followed by luteolin-7-O-glucoside (3.5 μg/mg) and 1,5-O-dicaffeoylquinic acid (1.07 μg/mg). The extract showed an inhibitory effect on CYP3A4 and CYP2C9 enzyme activities in control and diabetic rats.

Conclusions: The UHPLC-MS/MS-MRM method is sensitive and reliable for the quality control of V. amygdalina leaf extract. The inhibitory effect of the extract suggests that concomitant use of V. amygdalina leaf preparations with conventional drugs metabolized and eliminated from the body by CYP3A4 and CYP2C9 enzymes may lead to possible interaction.

Introduction: Pharmacogenetics (PGx) has the potential to improve patient care, allowing to transform medical interventions by providing personalized therapeutic strategies. Scientific evidence supports the use of PGx in clinical practice and international organizations are developing clinical guidelines to facilitate the utilization of PGx testing. However, clinical implementation of PGx is limited and unequal worldwide.

Content: This review summarizes regional and national Spanish initiatives to implement PGx in the clinical practice.

Summary and outlook: Diverse strategies to implement PGx in healthcare are applied across countries or even in the different regions of a specific country. Such was the case of Spain, a European country with 17 Autonomous Regions and two Autonomous Cities, each one with capacity to manage their own healthcare systems. Nevertheless, during the past years, many initiatives and strategies have been launched in Spain to develop different aspects of PGx. Importantly, the National Healthcare System has approved a PGx testing catalogue. This review highlights the crucial work and efforts of scientific societies (like the Spanish Society of Pharmacogenetics and Pharmacogenomics), of experts in PGx, of healthcare providers and of governmental parties in the implementation of PGx to personalize patient therapy, focused in Spain.

Objectives: Urinary tract infection (UTI) is one of the most frequent reasons for prescribing antibiotics. Escherichia coli implicated in 75-90 % cases of UTI is becoming increasingly resistant to antibiotics. Finding alternative therapeutic agent for this infection is critical, for which herbal drugs may be an option. In Unani medicine, urinary tract infection (Ṭa'diya Majra-i-Bawl) is treated with herbal drugs possessing Da'fe Ufoonat (antiseptic), Muhallilat (anti-inflammatory) and Mudirrat (diuretic) properties. Polyherbal formulations of such drugs are expected to be beneficial in treating Escherichia coli infection. The aim of the study was to assess the efficacy and safety of a Unani polyherbal formulation aimed to develop a safe and efficacious drug for the treatment of urinary tract infection (Ṭa'diya Majra-i-Bawl) caused by Escherichia coli.

Methods: This open-label, single armed clinical study was conducted on patients with clinical signs and symptoms of UTI and positive urine culture for E. coli. Patients were treated with the polyherbal formulation consisting of 50 % hydro-alcoholic extracts of Khar Khasak (Tribulus terrestris), Bhui Amla (Phyllanthus niruri), Kabab Cheeni (Piper cubeba), Beekh -i-Kasni (Cichorium intybus), Beekh-i-Karafs (Apium graveolens), Asl-us-Soos (Glycyrrhiza glabra), and Giloy (Tinospora cordifolia) in a dose of one capsule (500 mg) thrice a day orally with plain water for 42 days.

Results: Maximum (83 %) urine cultures turned out negative for E. coli after the completion of therapy.

Conclusions: Polyherbal Unani formulation was found to be very effective for the treatment of Urinary tract infection. Clinical and microbiological cure was achieved in maximum number of patients and drug was very well tolerated without any adverse/side effect.

Introduction: Testosterone, the primary male sex hormone, orchestrates various physiological processes including sex differentiation, development of male characteristics, sperm production, and fertility. Its synthesis primarily occurs in Leydig cells within the testes, with smaller contributions from the ovaries and adrenal glands, all derived from cholesterol. Current therapeutic use of testosterone is mainly confined to treating hypergonadotropic hypogonadism, with limited off-label usage for augmenting muscle growth.

Content: This review delves into numerous studies investigating testosterone's therapeutic potential across various medical conditions as depicted in the figure given below.

Summary: Of all the studies in this review, which show a positive therapeutic result by using testosterone, the most promising areas of potential usage of testosterone are anxiety and diabetes mellitus, followed by obesity and depression.

Outlook: By the medium if this study, we want to not only enlist the various potential therapeutic uses of testosterone, but also promote a optimal hormonal balance, which can lead to prevention and/or better treatment outcomes for the mentioned diseases.

Objectives: Ibuprofen, a widely used non-steroidal anti-inflammatory (NSAID) for managing pain and inflammation in pediatric patients, is metabolized by the CYP2C8 enzyme. Studies suggest that the CYP2C8*2, *3, and *4 variations of the CYP2C8 gene diminish ibuprofen metabolism, increasing the risk of adverse reactions. The aim of this study was to determine the frequency of the CYP2C8*2, *3, and *4 alleles and genotypes in a pediatric population attending the King Abdulaziz University dental clinic and compare our findings to those of other populations.

Methods: A cross-sectional study was conducted with 140 healthy Saudi children ages 6-12. Saliva samples were collected using Oragene™ DNA Sample Collection Kits and analyzed for polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results: The study identified that CYP2C8*2 AA, AT, and TT genotypes occurred at frequencies of 87.86 %, 9.29 %, and 2.86 %, respectively. For CYP2C8*3, AA, AG, and GG genotypes were found in 87.14 , 8.75, and 4.29 % of subjects, respectively. The CYP2C8*4 allele was less frequent, with CC and CG genotypes at 97.86 % and 2.14 %, respectively, and the GG genotype was absent. Allele frequencies for CYP2C8*2, *3, and *4 were 7.5 %, 8.57 %, and 1.07 %, respectively.

Conclusions: Our findings reveal that the allelic frequencies for the CYP2C8 polymorphisms in the Saudi pediatric cohort are substantially elevated compared to those reported in other Asian populations. This suggests Saudis may experience more varied drug responses, especially for medications that undergo metabolism by the CYP2C8 enzyme, like ibuprofen.

Objectives: Withania somnifera (WS) is a valuable medicinal plant that has been used against several ailments. The medicinal properties of WS are ascribed to existence of secondary metabolites which are in great demand in herbal nutraceutical industry. Despite well-known therapeutic effects of WS, it is necessary to assess preclinical toxicity of WS plant on rats and further explore its potential application against treatment of various disorders in humans. The existing study assessed oral acute and sub-chronic toxicities of WS root extract in Sprague Dawley (SD) rats (male and female) for 14 and 90 days, respectively under OECD-423 and -408 guidelines as well as GLP compliance.

Methods: In acute toxicity, rats of either sex were orally fed a dose of 2,000 mg/kg. In sub-chronic toxicity, animals were orally administered repeated doses of WS root extract at 250, 500, 1,000 mg/kg for 90 days with an additional 14-day recovery period. Two more groups (n=5 animals each) receiving vehicle and 1,000 mg/kg of WS root extract for 90 days were also observed.

Results: In acute toxicity, the results revealed that LD₅₀ of WS root extract in SD rats was higher than 2,000 mg/kg. In sub-chronic toxicity, oral administration of extract for 90 days showed no significant toxicological changes in rats. Haematological and serum chemistry markers were found within normal range. Terminal necropsy showed no gross or histopathological outcomes.

Conclusions: The no-observed-adverse-effect level (NOAEL) of WS root extract was 1,000 mg/kg body weight, and safe to use at this dose in rats.

Objectives: Withania somnifera (WS) is a valuable medicinal plant that has been used against several ailments. The medicinal properties of WS are ascribed to existence of secondary metabolites which are in great demand in herbal nutraceutical industry. Despite well-known therapeutic effects of WS, it is necessary to assess preclinical toxicity of WS plant on rats and further explore its potential application against treatment of various disorders in humans. The existing study assessed oral acute and sub-chronic toxicities of WS root extract in Sprague Dawley (SD) rats (male and female) for 14 and 90 days, respectively under OECD-423 and -408 guidelines as well as GLP compliance.

Methods: In acute toxicity, rats of either sex were orally fed a dose of 2,000 mg/kg. In sub-chronic toxicity, animals were orally administered repeated doses of WS root extract at 250, 500, 1,000 mg/kg for 90 days with an additional 14-day recovery period. Two more groups (n=5 animals each) receiving vehicle and 1,000 mg/kg of WS root extract for 90 days were also observed.

Results: In acute toxicity, the results revealed that LD₅₀ of WS root extract in SD rats was higher than 2,000 mg/kg. In sub-chronic toxicity, oral administration of extract for 90 days showed no significant toxicological changes in rats. Haematological and serum chemistry markers were found within normal range. Terminal necropsy showed no gross or histopathological outcomes.

Conclusions: The no-observed-adverse-effect level (NOAEL) of WS root extract was 1,000 mg/kg body weight, and safe to use at this dose in rats.