Drug metabolism and personalized therapy最新文献

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: 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.

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.