Drug metabolism and personalized therapy最新文献

Objectives: Leflunomide is a commonly used treatment for rheumatoid arthritis. It acts by inhibiting dihydroorotate dehydrogenase through its active metabolite teriflunomide. The objective of the study was to investigate the relation between plasma-concentration of teriflunomide and disease-activity in rheumatoid arthritis.

Methods: Data were collected from patients with rheumatoid arthritis on a stable leflunomide dose for at least 2 months. Socio-demographic data, disease characteristics and DAS28 score were recorded. Blood samples were taken for determination of teriflunomide concentration.

Results: A total of 32 serum concentration-time measurements were collected. The concentration of teriflunomide was positively correlated with disease duration of RA (r²=0.2264) and the number of swollen joints (r²=0.2413). There was a trend towards a positive correlation between Health Assessment Questionnaire (HAQ) and plasma teriflunomide concentration (r²=0.1699). Weight was negatively correlated with the residual plasma concentration of teriflunomide (r²=0.2483). However, there was no significant correlation between residual-plasma-concentration of teriflunomide and the following parameters: age, sex, number of tender painful joints, patient-global-assessment, C-reactive protein (CRP) and duration of prescription of leflunomide. We did not find association between disease-activity and residual-plasma-concentration of teriflunomide (r²=0.0021) and haven't been able to define the threshold value of residual-plasma-concentration of leflunomide predictive of a good-response.

Conclusions: We did not find a concentration-effect-relationship. However, therapeutic drug monitoring of teriflunomide may be useful to ensure adherence and evaluate toxic-levels in case of adverse-events.

Objectives: To analyze the phytochemicals, antioxidant, and anticancer activities on MCF-7 human breast cancer cell line using aqueous, hydro-ethanol, and methanol extracts of different Unani drugs, e.g., Halela Siyah, Aftimoon, Bisfayej, Ustukhudoos, and Kutki.

Methods: The qualitative examination (alkaloids, terpenoids, tannins, and saponins), anticancer activity, and an antioxidant assay of the three different extracts were done by MTT assay and DPPH assay, respectively, using different Unani drugs.

Results: The qualitative examination confirmed the substantive presence of phytochemical constituents in all the extracts of these drugs. The Methanolic extract of Halela Siyah had the highest DPPH scavenging activity (91%), while Bisfayej had the lowest (58%). Similarly, the hydro-ethanolic extract showed approximately identical activity for Halela Siyah (89%), Aftimoon (88%), Bisfayej (84%), Kutki (82%), and Ustukhudoos (81%). The aqueous extracts of Halela Siyah (88%) had the highest DPPH scavenging activity, whereas Bisfayej (73%) had the lowest. The methanolic extract of Aftimoon demonstrated the greatest anticancer activity (IC₅₀ - 108), while Aftimoon showed the least activity (IC₅₀ - 316). Halela Siyah (IC₅₀ - 175) and Aftimoon (IC₅₀ - 178) showed substantially the same activity in aqueous extracts. Ustukhudoos hydro-ethanol extracts had the highest (IC₅₀ - 130) activity, whereas Aftimoon had the lowest (IC₅₀ - 204).

Conclusions: In conclusion, our findings evaluated the presence of phytochemicals, good antioxidant activity, and anticancer activity in different extracts of drugs used in this study. The study shows these drugs have potential anticancer activity against breast cancer in MCF-7 cell lines.

Viruses are obligatory protein-coated units and often utilize the metabolic functions of the cells they infect. Viruses hijack cellular metabolic functions and cause consequences that can range from minor to devastating, as we have all witnessed during the COVID-19 pandemic. For understanding the virus-driven pathogenesis and its implications on the host, the cellular metabolism needs to be elucidated. How SARS-CoV-2 triggers metabolic functions and rewires the metabolism remains unidentified but the implications of the metabolic patterns are under investigation by several researchers. In this review, we have described the SARS-CoV-2-mediated metabolic alterations from in vitro studies to metabolic changes reported in victims of COVID-19. We have also discussed potential therapeutic targets to diminish the viral infection and suppress the inflammatory response, with respect to evidenced studies based on COVID-19 research. Finally, we aimed to explain how we could extend vaccine-induced immunity in people by targeting the immunometabolism.

Objectives: Clinical Pharmacogenetics Implementation Consortium (CPIC) is a platform that advances the pharmacogenomics (PGx) practice by developing evidence-based guidelines. The purpose of this study was to analyze the CPIC database for ADME related genes and their corresponding drugs, and evidence level for drug-gene pairs; and to determine the presence of these drug-gene pairs in the highest mortality diseases in the United States.

Methods: CPIC database was evaluated for drug-gene pairs related to absorption, distribution, metabolism, and excretion (ADME) properties. National Vital Statistics from Centers for Disease Control and Prevention was used to identify the diseases with the highest mortality. CPIC levels are assigned to different drug-gene pairs based on varying levels of evidence as either A, B, C, or D. All drug-gene pairs assigned with A/B, B/C, or C/D mixed levels were excluded from this study. A stepwise exclusion process was followed to determine the prevalence of various ADME drug-gene pairs among phase I/II enzymes or transporters and stratify the drug-gene pairs relevant to different disease conditions most commonly responsible for death in the United States.

Results: From a total of 442 drug-gene pairs in the CPIC database, after exclusion of 86 drug-gene pairs with levels A/B, B/C, or C/D, and 211 non-ADME related genes, 145 ADME related drug-gene pairs resulted. From the 145 ADME related drug-genes pairs, the following were the distribution of levels: Level A: 43 (30%), Level B: 22 (15%), Level C: 59 (41%), Level D: 21 (14%). The most prevalent ADME gene with CPIC level A classification was cytochrome P450 2C9 (CYP2C9) (26%) and overall, the most prevalent ADME gene in the CPIC database was CYP2D6 (30%). The most prevalent diseases related to the CPIC evidence related drugs were cancer and depression.

Conclusions: We found that there is an abundance of ADME related genes in the CPIC database, including in the high mortality disease states of cancer and depression. There is a differential level of pharmacogenomic evidence in drug-gene pairs enlisted in CPIC where levels A and D having the greatest number of drug-gene pairs. CYP2D6 was the most common ADME gene with CPIC evidence for drug-gene pairs. Pharmacogenomic applications of CPIC evidence can be leveraged to individualize patient therapy and lower adverse effect events.

Objectives: The development of new methods for determining the concentration of drugs is an actual topic today. The article contains a detailed review on vibrational spectroscopy and nuclear magnetic resonance methods using for pharmacokinetic research. This study is devoted to the possibility of using vibrational spectroscopy and 1H nuclear magnetic resonance spectroscopy to determine the concentration of drugs and the use of these groups of techniques for therapeutic drug monitoring.

Content: The study was conducted by using scientific libraries (Scopus, Web of Science Core Collection, Medline, GoogleScholar, eLIBRARY, PubMed) and reference literature. A search was conducted for the period from 2011 to 2021 in Russian and English, by combinations of words: 1H nuclear magnetic resonance (¹H NMR), vibrational spectroscopy, Surface-Enhanced Raman spectroscopy, drug concentration, therapeutic drug monitoring. These methods have a number of advantages and are devoid of some of the disadvantages of classical therapeutic drug monitoring (TDM) methods - high performance liquid chromatography and mass spectrometry. This review considers the possibility of using the methods of surface-enhanced Raman scattering (SERS) and ¹H NMR-spectroscopy to assess the concentration of drugs in various biological media (blood, urine), as well as to study intracellular metabolism and the metabolism of ophthalmic drugs. ¹Н NMR-spectroscopy can be chosen as a TDM method, since it allows analyzing the structure and identifying metabolites of various drugs. ¹Н NMR-based metabolomics can provide information on the side effects of drugs, predict response to treatment, and provide key information on the mechanisms of action of known and new drug compounds.

Summary and outlook: SERS and ¹Н NMR-spectroscopy have great potential for further study and the possibility of introducing them into clinical practice, including for evaluating the efficacy and safety of drugs.

Objectives: The use of detergent-action drugs in traditional Unani therapeutic intervention has been a long-standing Unani medicinal practice. The key aim of the article is to provide thorough information on the novel, unexplored idea of Unani Jali (detergent/cleansers) drugs for the treatment of skin ailments, as well as to identify medicinal plants that have detergent action and correlate these findings with scientific studies that may support evidence for the drug's detergent effect.

Content: The ethnobotanical classical literature of Unani medicine was investigated in order to have a comprehensive insight of Unani detergents/cleansers. Scientific studies were carried from databases including PubMed, Scopus, Science Direct, and google Scholar, among others. More than fifty exclusive plant, mineral, and animal-based detergents are found specifically for skin disorders in Unani therapy. These drugs basically evacuate impurities from the body's excretory system and and have been found to have keratolytic and debris-peeling effects, as well as the ability to maintain skin tone consistency. Unani Jali drugs have also been found to have anti-inflammatory, antibacterial, analgesic, and tonic properties, suggesting its usefulness holistically.

Summary and outlook: Based on phyto constituents, prospective therapeutic response, and scientific data, this review proposes that Unani Jali drugs could be a safe and promising therapeutic option for dermatological illnesses such as vitiligo, acne, dermatitis, psoriasis, and skin sensitivity.

Objectives: Dry cupping therapy (DCT) is considered beneficial in the amelioration of cervical spondylosis (CS) symptoms in Unani medicine. Therefore, the focus of this study was to ascertain the efficacy of DCT and optimal cup application time duration for CS.

Methods: It was a randomized clinical trial involving 45 participants with clinically diagnosed CS. The eligible subjects were randomly categorized into three groups, each having 15 participants. Each of the three groups, i.e., A, B, and C, received DCT daily for 15 days for 8 min, 10 min, and 12 min, respectively. All the participants were evaluated at the baseline, 7th, and 15th days of the trial using the neck disability index (NDI) as well as the visual analogue scale (VAS).

Results: The baseline mean ± SD of NDI and VAS scores were significantly reduced in all the three groups at the end of the trial. Although all three groups were statistically equal in terms of NDI, group-C demonstrated greater efficacy in terms of VAS.

Conclusions: The per-protocol analysis showed that dry cupping effectively alleviated neck pain across all treatment groups. Although, this effect on neck disability index was statistically equal in all three groups, the 12-min protocol was more successful in reducing pain.

Objectives: Therapy failure caused by complex population-drug-drug (PDDI) interactions including CYP3A4 can be predicted using mechanistic physiologically-based pharmacokinetic (PBPK) modeling. A synergy between ritonavir-boosted lopinavir (LPVr), ivermectin, and chloroquine was suggested to improve COVID-19 treatment. This work aimed to study the PDDI of the two CYP3A4 substrates (ivermectin and chloroquine) with LPVr in mild-to-moderate COVID-19 adults, geriatrics, and pregnancy populations.

Methods: The PDDI of LPVr with ivermectin or chloroquine was investigated. Pearson's correlations between plasma, saliva, and lung interstitial fluid (ISF) levels were evaluated. Target site (lung epithelial lining fluid [ELF]) levels of ivermectin and chloroquine were estimated.

Results: Upon LPVr coadministration, while the chloroquine plasma levels were reduced by 30, 40, and 20%, the ivermectin plasma levels were increased by a minimum of 425, 234, and 453% in adults, geriatrics, and pregnancy populations, respectively. The established correlation equations can be useful in therapeutic drug monitoring (TDM) and dosing regimen optimization.

Conclusions: Neither chloroquine nor ivermectin reached therapeutic ELF levels in the presence of LPVr despite reaching toxic ivermectin plasma levels. PBPK modeling, guided with TDM in saliva, can be advantageous to evaluate the probability of reaching therapeutic ELF levels in the presence of PDDI, especially in home-treated patients.

Objectives: Symptomatic remediation from attention deficit hyperactivity disorder (ADHD)-associated traits is achieved by treatment with methylphenidate (MPH)/atomoxetine (ATX). We have analyzed the association of functional CYP2D6 variations, rs1065852, rs3892097, rs1135840, and rs1058164, with ADHD in the Indian subjects.

Methods: Subjects were recruited following the Diagnostic and Statistical Manual for Mental Disorders. Trait scores were obtained from the Conner's Parents Rating Scale-Revised. After obtaining informed consent, blood was collected for DNA isolation, and genotyping was performed by PCR or TaqMan-based methods. Probands were treated with MPH or ATX based on age, symptoms, and drug availability. Treatment outcome was assessed using a structured questionnaire. Data obtained was analyzed to identify the association of CYP2D6 variations and the SLC6A3 rs28363170 with the treatment outcome.

Results: The frequency of rs1135840 "G" and rs1065852 "G" was higher in the male ADHD probands. Bias in parental transmission (p=0.007) and association with higher trait scores were observed for rs1065852 "A". Independent influence of rs1065852 on ADHD was also observed. Probands carrying rs1065852 'GG', rs1135840 'CG', and rs28363170 10R exhibited significant symptomatic improvement with MPH, while probands with rs1135840 'CC' and rs28363170 9R showed improvement after ATX treatment.

Conclusions: ADHD probands having specific CYP2D6 genetic variations respond differentially to pharmaceutical intervention.