Drug metabolism and personalized therapy最新文献

Individual variations in the response to thiopurine-based anticancer drugs are influenced by genetic and environmental factors, making it challenging to optimize dosing and minimize toxicity. Among the key genes involved, genetic variations in the nudix hydrolase 15 (NUDT15) gene affect on thiopurine metabolism, thus influencing drug efficacy and the risk of severe adverse effects, such as myelosuppression, These variations also contribute to inter-individual differences in drug tolerance and clinical outcomes. Despite the recognized impact of NUDT15 variations, there has been limited comprehensive exploration of these variants and their clinical significance in thiopurine therapy. This review provides a thorough analysis of NUDT15 genetic variants by synthesizing findings from prior clinical studies and employing in silico analyses to predict the functional effects of variants with uncertain significance. Comprehensive analysis of NUDT15 variants and their interactions with other metabolic pathways could offer valuable insights for advancing personalized medicine in cancer treatment. This review aims to establish a foundation for integrating NUDT15 genetic information into the clinical practice, reducing toxicity, and improved therapeutic outcomes in patients undergoing thiopurine-based chemotherapy.

Objectives: Primary hypothyroidism is a prevalent endocrine disorder, typically treated with levothyroxine (LT). However, prolonged use of LT may result in complications and suboptimal outcomes for some patients. Majoone Sarkhas (MS), is a polyherbal formulation comprises four plants: Commiphora mukul, Operculina turpethum, Embelia tseriam-cottam, and Dryopteris filix-mas. It is traditionally used in Unani medicine for managing hypothyroidism associated conditions. The aim of this study was to assess the synergistic effect of Majoone Sarkhas in combination with LT for the treatment of primary hypothyroidism.

Methods: This randomized, single blind, standard clinical trial involved 100 subjects allocated into two groups: an adjuvant treatment group (n=50) and a standard control group (n=50). The adjuvant group received 10 g of MS twice daily in addition LT once daily, while the control group was treated with LT alone once daily. Both groups underwent treatment for 60 days. Changes in thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), and free-thyroxine (FT4) levels from baseline to the 60th day were recorded and analyzed statistically to evaluate the outcomes.

Results: The study showed adjuvant group (MS + LT) had more reduction (4.99 vs. 3.93) in serum TSH level in comparison to control group (LT), which was statistically significant (p<0.001), it also showed increase in serum FT3 (2.88 ± 0.31 vs. 2.97 ± 0.44) and FT4 (1.06 ± 0.17 vs. 1.20 ± 0.27) levels, when compared with baseline values and after completion of trial.

Conclusions: The change in thyroid function profiles among adjuvant group, receiving MS with LT in primary hypothyroidism was both clinically and statistically significant. The safety parameters those were followed by serum level of ALT, AST, blood urea and serum creatinine were within the range, indicating the MS is safe medication to be used as an adjuvant therapy with LT (Clinical Trial Registration Code: CTRI/2018/02/011962).

Objectives: Withania somnifera (WS), also known as Ashwagandha, is a health-beneficial Ayurvedic medicinal plant with great potential as an adaptogen with rejuvenating and anti-aging effects. However, studies investigating pharmacokinetics (PK), safety, and tolerability of WS on humans are limited. The present study evaluated PK, safety, and tolerability of WS root extract (2.5 % total withanolides) capsules upon oral administration of two capsules of 200 mg each (total 400 mg) in healthy male and female volunteers.

Methods: An open label, single dose, clinical design comprising healthy volunteers was employed. The study evaluated PK parameters of the four bioactive constituents viz. withanoside IV, withaferin A, 12-deoxy-withastramonolide, and withanolide A in WS root extract after analysis of plasma using a validated UHPLC-MS/MS method. Further, safety and tolerability assessment for vital signs, testing for organ function, urine examination, X-ray, ECG, as well as adverse events profile were also investigated.

Results: After oral administration of 2 WS capsules (200 mg each), the participants reported normal physical, hematological, and biochemical parameters with no abnormalities in safety metrics. For the four bioactives, the exposure parameters range between 0.472 and 4.468 ng/mL (C_max), 1.000-1.416 h (T_max), and 2.051-13.319 ng/mL*h (AUC 0-t). Further, t_1/2 (1.696-4.377 h), lambda_z (0.141-0.282 L/h), Cl/F (0.065-0.954 mg/(ng/ml)/h), AUMC 0-inf_obs (21.720-80.485 ng/mL*hˆ2) and MRT 0-inf_obs (3.680-7.516 h) also differed for each bioactive.

Conclusions: The present study elucidated the PK of WS and showed that healthy male and female volunteers may safely consume WS capsules at a dose of 400 mg (2 capsules of 200 mg) without any harmful effects.

Objectives: The clinical outcomes of tamsulosin therapy for LUTS/BPH patients vary, with up to one-third of patients reporting unsatisfactory results. Enhancing the effectiveness and safety of tamsulosin therapy for LUTS/BPH patients remains a significant challenge in current medical practice. Limited data exists regarding the impact of CYP2D6 genetic polymorphisms on the efficacy and safety of tamsulosin therapy. Given that tamsulosin is metabolized by CYP2D6, variations in this enzyme may influence the drug's pharmacodynamic response. The objective of this study was to evaluate the impact of CYP2D6 pharmacogenetic markers on tamsulosin efficacy and safety in patients with LUTS associated with BPH.

Methods: The study included 142 male patients with LUTS and a confirmed diagnosis of BPH (N40 ICD-10). Patients were followed for a minimum of 8 weeks and underwent four examinations (at days 0, 14, 28, and 56). Treatment efficacy was assessed using the IPSS with quality of life assessment, transrectal ultrasound of the prostate with estimation of prostate volume and residual urine volume, and maximum urinary flow rate (Qmax). Allelic variants of CYP2D6 (*2, *3, *4, *6, *9, *10, and *41) were determined by polymerase chain reaction in all patients..

Results: In the subgroup with moderate symptoms, individuals classified as poor and intermediate metabolizers exhibited significantly higher ΔQmax compared to normal metabolizers (4.25 [2.5; 6.1] vs. [0.6; 4.3], p=0.001826). Moreover, carriers of the CYP2D6*10 CT heterozygous genotype demonstrated lower IPSS scores at the last two visits compared to those with the CC genotype (visit 3: -7.45 ± 3.93 vs. -5.25 ± p=0.05; visit 4: -8.91 ± 3.88 vs. -6.31 ± 5.7), as well as reduced IPSS irritative symptoms at visit 2 (-3.87 ± 2.70 vs -2.47 ± 3.1, p=0.05), and a significant increase in ΔQmax ([2.5; 5.9] vs. [0.6; 4.7], p=0.01). In the subgroup with severe symptoms, individuals with CYP2D6*41 GA + AA genotypes exhibited less residual urine volume following therapy compared to those with the GG genotype ([15.0; 32.0] vs. [3.0; 19.0], p=0.007029). The CYP2D6 polymorphic variants did not impact the tamsulosin safety. The study did not reach the estimated power for CYP2D6*3, CYP2D6*6, and CYP2D6*9 polymorphisms due to their low frequency of occurrence in the study population. The multivariate logistic regression model indicated that potential predictors of tamsulosin therapy efficacy in LUTS/BPH patients may include BMI (p<0.001), prostate volume (p<0.002), as well as the carriage of CYP2D6*4 (p<0.001) and CYP2D6*10 (p=0.012) markers. The model explained 81.9 % of the variance in the predicted outcome and accurately forecasted tamsulosin therapy efficacy in BPH with a precision of 92.1 %.

Conclusions: The present study identified potential markers that could serve as p

Objectives: There is an inter-individual in the valsartan response among hypertensive patients. However, clinical factors associated with this variation in the response is still not fully understood. The major purpose of this study is to predict the factors associated with valsartan response and their influence on decreasing blood pressure among patients.

Methods: This study is a cross-sectional observational study. It included 91 hypertensive patients on valsartan treatment, selected through simple random sampling from the Jordan University Hospital. The clinical data was collected through documented medical records in the hospital's computerized system. The data was analyzed using the chi-square test to compare frequencies and categories.

Results: Patients were divided into systolic and diastolic responders. No statistical significance was found between systolic response to valsartan's and gender, smoking, age, BMI, lipid profile and HbA_1c status. Diastolic responders had a positive significance of p-value = 0.006 with BMI categories, however there was no significance with any other factor.

Conclusions: There was a better diastolic response to valsartan among hypertensive patients with lower BMI levels. BMI can be considered as a factor to personalize the therapy among patients on valsartan. However, further clinical studies with larger sample size are needed to confirm these data.

Objectives: This study intended to investigate the potential of glucosamine sulfate (GS) as an inhibitor of genes involved in osteoarthritis (OA) development. Despite GS is often used for OA treatment due to its cartilage preservation and minimum side effects, the molecular mechanism behind its interactions remains unknown.

Methods: Molecular docking was conducted to analyze the interactions between glucosamine sulfate and genes associated with OA such as matrix metalloproteinase-3 (MMP-3), MMP-9, and interleukin-4 (IL-4). Additionally, a cell viability assay using RAW 264.7 cells was performed to evaluate the toxicity of glucosamine sulfate at various concentrations.

Results: Molecular docking results revealed that glucosamine sulfate has a good binding affinity and stable interactions with MMP-3, MMP-9, and IL-4, indicating that it may have inhibitory effects on targeted genes. Nevertheless, the cell viability assay analysis demonstrated that glucosamine sulfate had considerable toxic effects in RAW 264.7 cells at highest concentrations.

Conclusions: Glucosamine sulfate exhibited stable molecular interactions with genes associated to OA development. However, GS toxicity at high concentrations necessitates future research studies to optimize dosing and assess its therapeutic safety in OA treatment.

Objectives: To explore pain outcomes in patients prescribed hydrocodone and psychotropic medications with or without CYP2D6 inhibition activity.

Methods: Patients hospitalized for lower/limited upper extremity injuries who were prescribed hydrocodone alongside a psychotropic medication were considered for this study (n=224). A subset of these patients (n=178) was prescribed a psychotropic medication known to inhibit CYP2D6, while the remainder (n=46) were prescribed psychotropic medications without CYP2D6 inhibition activity. Patient demographics and pain outcomes were collected by electronic health record review and interviews.

Results: Patients taking a psychotropic inhibitor of CYP2D6 exhibited longer duration of opioid use post-discharge (median 33 days [IQR 10-99]) compared with patients taking a psychotropic non-inhibitor (4 days [2-20], p<0.001). No significant differences were observed with in-hospital pain outcomes, including total dose of hydrocodone administered, duration of hydrocodone use, pain index scores, and the occurrence of common mild/moderate/severe hydrocodone side effects.

Conclusions: Patients prescribed at least one psychotropic inhibitor of CYP2D6 were more likely to continue using hydrocodone for up to 3 months following surgery. Knowledge of these critical drug-drug interactions could enhance clinical practice and improve patient outcomes. This study highlights negative post-operative pain outcomes in patients prescribed hydrocodone alongside a psychotropic inhibitor of CYP2D6. The results of this study indicate that patients taking psychotropic medications that inhibit CYP2D6 are at increased risk for prolonged hydrocodone use following orthopedic surgery.