Changes In Drug Metabolism Research Articles

Redefining space pharmacology: bridging knowledge gaps in drug efficacy and safety for deep space missions

The space environment is incredibly hostile, and humans are vulnerable in such conditions. Astronauts encounter various stress factors during a space journey, including radiation, microgravity, forceful acceleration during launch, altered magnetic fields, and confinement. These stressors significantly impact the human body homeostasis, leading to physio-pathological adaptations, loss of bone density, muscle atrophy, cardiovascular deconditioning, alterations in liver function, vestibular adaptations, and immune system dysregulation. These alterations can potentially influence drug pharmacokinetics and pharmacodynamics, affecting the efficacy and safety of medications administered to astronauts. Due to the limited number of studies on pharmaceuticals conducted in microgravity conditions, it’s challenging to assess the effectiveness and stability of these medications during spaceflight. The objective of the present work is to compare the state-of-the-art knowledge on PK/PD changes and factors likely to affect them during spaceflight, with the subjective perception of the problem by a collection of separate interviews conducted with seven experts in the field. The interviewees were chosen as “experts,” i.e., representatives in a specific discipline, who possess knowledge and experience in space pharmacology, physiology, or biology. Thus, our panel included astronauts, space surgeons, and scientists aiming to bridge the lack of experimental data in the literature. Each interview explores assorted aspects of space physiology and pharmacology, including drug use and storage onboard the ISS; notable consideration has arisen regarding the current research gaps and future space expeditions. All the interviews were held remotely using online conferencing software. None of the interviewees could provide a comprehensive overview regarding potential changes in drugs PK/PD in microgravity conditions. Further, any medication brought on board (whether as part of an astronaut’s medical kit or stored in the ISS pharmacy) is destroyed, thereby suppressing the possibility of analyzing any degradation products resulting from long-term exposure to microgravity and radiation. According to these results, the use of drugs without understanding how they are genuinely absorbed, distributed, metabolized, and excreted in microgravity conditions is concerning, posing risks for drug effectiveness. Conducting genotyping and phenotyping on astronauts would be beneficial for developing personalized pharmacological countermeasures for each astronaut and anticipating expected drug metabolism changes during space missions.

Non-additivity of the functional properties of individual P450 species and its manifestation in the effects of alcohol consumption on the metabolism of ketamine and amitriptyline

To explore functional interconnections between multiple P450 enzymes and their manifestation in alcohol-induced changes in drug metabolism, we implemented a high-throughput study of correlations between the composition of the P450 pool and the substrate saturation profiles (SSP) of amitriptyline and ketamine demethylation in a series of 23 individual human liver microsomes preparations from donors with a known history of alcohol consumption. The SSPs were approximated with linear combinations of three Michaelis-Menten equations with globally optimized KM (substrate affinity) values. This analysis revealed a strong correlation between the rate of ketamine metabolism and alcohol exposure. For both substrates, alcohol consumption caused a significant increase in the role of the low-affinity enzymes. The amplitudes of the kinetic components and the total rate were further analyzed for correlations with the abundance of 11 major P450 enzymes assessed by global proteomics. The maximal rate of metabolism of both substrates correlated with the abundance of CYP3A4, their predicted principal metabolizer. However, except for CYP2D6 and CYP2E1, responsible for the low-affinity metabolism of ketamine and amitriptyline, respectively, none of the other potent metabolizers of the drugs revealed a positive correlation. Instead, in the case of ketamine, we observed negative correlations with the abundances of CYP1A2, CYP2C9, and CYP3A5. For amitriptyline, the data suggest inhibitory effects of CYP1A2 and CYP2A6. Our results demonstrate the importance of functional interactions between multiple P450 species and their decisive role in the effects of alcohol exposure on drug metabolism.

COSMIC Database and Structural Modeling Analysis of CYP2D6 Mutations in Human Cancers.

Single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) enzymes alter the metabolism of a variety of drugs. Numerous medications, including chemotherapies, are metabolized by CYP450 enzymes, making the expression of this suite of enzymes in tumor cells relevant to prescription regimens for cancer patients. We analyzed the characteristics of mutations of the CYP2D6 enzymes in cancer patients obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC), including mutation type, age of the patient, tissue type, and histology. Mutations were analyzed through the Cancer-Related Analysis of Variants Toolkit (CRAVAT) software along with CHASM and VEST4 algorithms to determine the likelihood of being a driver and/or pathogenic mutation. For mutations with significant CHASM and VEST4 scores, structural analysis of each corresponding mutant protein was performed. The effect of each mutation was evaluated for its impact on the overall protein stability and ligand binding using Foldit Standalone and SwissDock, respectively. Structural analysis revealed that several missense mutations in CYP2D6 resulted in altered stability after energy minimization. Three missense mutations of CYP2D6 significantly altered docking stability and those located on alpha-helices near the docking site had a more significant impact than those not found in secondary protein structures. In conclusion, we have identified a series of mutations to CYP2D6 enzymes with possible relevance to cancer pathologies. Significance Statement CYP2D6 is responsible for the metabolism of many anti-cancer drugs. This study identified and characterized a series of mutations in the CYP2D6 enzyme that occurred in tumors. We found it likely that many of these mutations would alter enzyme function, leading to changes in drug metabolism in the tumor. We provide a basis for predicting the likelihood of a patient carrying these mutations to identify patients who may benefit from a precision medicine approach to drug selection and dosing.

Pharmacist-Led Video Consultation to Identify and Mitigate Drug Interactions Among Patients Initiating Oral Anticancer Drugs.

The past decade has seen an increase in oral anticancer drug (OACD) approvals. Polypharmacy and drug-drug interactions (DDIs) likely contribute to OACD toxicity. We assessed a one-time pharmacist-led video consultation to identify DDIs. We conducted a single-arm telehealth intervention of a one-time 30-minute pharmacist-led video consultation among patients initiating OACDs. The visit focused on identifying polypharmacy and DDIs. Feasibility was defined as ≥50% completion of all study interventions. We determined the prevalence, characteristics, and severity of OACD-related potential DDIs. We also assessed the prevalence of medication list inaccuracies, polypharmacy, patient satisfaction, and patient perception of intervention acceptability, appropriateness, and feasibility. Of 58 eligible patients, 43 (74%) completed the intervention and 33 (57%) completed all evaluations. Median medication per patient was nine (range 4-21), and 98% of patients had at least five prescriptions. The median number of medication list errors was two (range 0-16), with at least one error for 76% and >1 for 52%. Pharmacists identified OACD-related interactions in 18 cases (42%), including change in drug metabolism (eight), elimination (one), and absorption (three). Interactions were classified as Lexicomp categories C (13), D (five), or X (one) requiring close monitoring or a change in treatment. All patients expressed high satisfaction with the intervention and agreed or completely agreed that it was acceptable, appropriate, and feasible. Polypharmacy, medication list errors, and DDIs are prevalent among patients initiating OACDs. A one-time remote pharmacist-led video consultation can address OACD-related DDIs, which may decrease medication complexity and improve adherence.

A web-based scoping review assessing the influence of smoking and smoking cessation on antidiabetic drug meabolism: implications for medication efficacy.

Currently 1.3 billion individuals globally engage in smoking, leading to significant morbidity and mortality, particularly among diabetic patients. There is urgent need for a better understanding of how smoking influences antidiabetic treatment efficacy. The review underscores the role of cigarette smoke, particularly polycyclic aromatic hydrocarbons (PAHs), in modulating the metabolic pathways of antidiabetic drugs, primarily through the induction of cytochrome P450 (CYP450) enzymes and uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), thus impacting drug pharmacokinetics and therapeutic outcomes. Furthermore, the review addresses the relatively uncharted territory of how smoking cessation influences diabetes treatment, noting that cessation can lead to significant changes in drug metabolism, necessitating dosage adjustments. Special attention is given to the interaction between smoking cessation aids and antidiabetic medications, a critical area for patient safety and effective diabetes management. This scoping review aims to provide healthcare professionals with the knowledge to better support diabetic patients who smoke or are attempting to quit, ensuring tailored and effective treatment strategies. It also identifies gaps in current research, advocating for more studies to fill these voids, thereby enhancing patient care and treatment outcomes for this at-risk population.

Multifaceted role of erlotinib in various cancer: nanotechnology intervention, patent landscape, and advancements in clinical trials.

Erlotinib (ELB) is a tyrosine kinase inhibitor that targets the activity of Epidermal Growth Factor Receptor (EGFR) protein found in both healthy and cancerous cells. It binds reversibly to the ATP-binding site of the EGFR tyrosine kinase. ELB was approved by the US Food and Drug Administration (FDA) in 2004 for advanced non-small cell lung cancer (NSCLC) treatment in patients who relapsed after at least one other therapy. It was authorized for use with gemcitabine in 2005 for the treatment of advanced pancreatic cancer. In addition to lung cancer, ELB has shown promising results in the treatment of other cancers, including breast, prostate, colon, pancreatic, cervical, ovarian, and head and neck cancers. However, its limited water solubility, as a BCS class II drug, presents biopharmaceutical problems. Nanoformulations have been developed to overcome these issues, including increased solubility, controlled release, enhanced stability, tumor accumulation, reduced toxicity, and overcoming drug resistance. In older patients, ELB management should involve individualized dosing based on age-related changes in drug metabolism and close monitoring for adverse effects. Regular assessments of renal and hepatic functions are essential. This review provides an overview of ELB's role of ELB in treating various cancers, its associated biopharmaceutical issues, and the latest developments in ELB-related nanotechnology interventions. It also covers ELB patents granted in previous years and the ongoing clinical trials.

Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

A Review of the Association between Infections, Seizures, and Drugs.

Seizures are a common presenting symptom of the central nervous system (CNS) and could occur from infections (such as toxins) or drugs. The aim of this study was to present a systematic review of the association between infections, seizures, and drugs. Through February 18, 2024, according to the PRISMA guidelines and based on the PICO standard format, relevant, in-depth consequent guide approach and evidence-based options were selected associated with a knowledgeable collection of current, high-quality manuscripts. Imbalance between inhibitory and excitatory neurotransmitters due to infections, drugs such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, tramadol, venlafaxine, cyclosporine, tacrolimus, acyclovir, cellcept, the old generation of antiepileptic drugs, such as carbamazepine, phenytoin, and many other drugs could cause different stages of CNS disturbances ranging from seizure to encephalopathy. Infections could cause life-threatening status epilepticus by continuous unremitting seizures lasting longer than 5 minutes or recurrent seizures. Meningitis, tuberculosis, herpes simplex, cerebral toxoplasmosis, and many others could lead to status epilepticus. In fact, confusion, encephalopathy, and myoclonus were reported with drugs, such as ticarcillin, amoxicillin, oxacillin, penicillin G, ampicillin, and others. Penicillin G was reported as having the greatest epileptogenic potential. A high dose, in addition to prolonged use of metronidazole, was reported with seizure infection. Meropenem could decrease the concentration of valproic acid. Due to the inhibition of cytochrome P450 3A4, the combination of clarithromycin and erythromycin with carbamazepine needs vigilant monitoring. Due to changes in drug metabolism, co-administration of antiseizure drugs and antibiotics may lead to an enhanced risk of seizures. In patients with neurocysticercosis, cerebral malaria, viral encephalitis, bacterial meningitis, tuberculosis, and human immunodeficiency virus, the evidence-based study recommended different mechanisms mediating epileptogenic properties of toxins and drugs.

Dental implications of childhood obesity and prevention and management methods in dental office

Childhood obesity is a common chronic disease in childhood, and its prevalence and socioeconomic costs have increased worldwide over the past 40 years. The World Health Organization has designated obesity as a global epidemic, emphasizing the need for its treatment and management. The impacts of childhood obesity on dentistry include a higher risk of dental caries, advanced dental development, as well as psychological changes (anxiety, depression, attention deficit hyperactiv-ity disorder) and physical changes (increased complications, changes in drug metabolism) that should be considered when implementing preventive strategies, orthodontic treatment, behavior management and sedative procedures. Dentists should regularly check child’s body mass index and diet for every child visiting dental office. Parental obesity, consumption of sugar-sweetened beverages, poor dietary habits, and lack of exercise can be a risk factors for obesity in normal/overweight child. Diet counseling should be provided to high-risk children and their parents. Preventing childhood obesity is crucial, and the key point in treating childhood obesity is behavior modification therapy, which focuses on regulating daily eatinghabits and physical activity. Dentists should recognize the seriousness of childhood obesity and participate in the prevention and management of the obesity epidemic, thus enhancing oral and systemic health

Epigenetic regulation of drug metabolism in aging: utilizing epigenetics to optimize geriatric pharmacotherapy.

We explore the relationship between epigenetic aging and drug metabolism. We review current evidence for changes in drug metabolism in normal aging, followed by a description of how epigenetic modifications associated with age can regulate the expression and functionality of genes. In particular, we focus on the role of epigenome-wide studies of human and mouse liver in understanding these age-related processes with respect to xenobiotic processing. We highlight genes encoding drug metabolizing enzymes and transporters revealed to be affected by epigenetic aging in these studies. We conclude that substantial evidence exists for epigenetic aging impacting drug metabolism and transport genes, but more work is needed. We further highlight the promise of pharmacoepigenetics applied to enhancing drug safety in older adults.

Feasibility and efficacy of a pharmacist-led video consultation to identify drug interactions among patients initiating oral anti-cancer drugs.

405 Background: The past decade has seen a dramatic increase in the number oral anti-cancer drug (OACD) approvals in the U.S. Though polypharmacy and drug-drug interactions (DDIs) likely contribute to OACD toxicity, the prevalence of these features in patients on OACDs remains largely unknown. We aimed to assess the feasibility and preliminary efficacy of a one-time 30-minute pharmacist-led video consultation among cancer patients initiating OACDs. Methods: We conducted a single-arm, prospective telehealth intervention study among patients initiating OACDs to assess the feasibility and preliminary efficacy of a one-time 30-minute pharmacist-led video consultation. The video visit focused on identifying potential DDIs, and pharmacists then communicated recommendations to the oncologist. Feasibility was defined as ≥ 60% completion of the pharmacist-led video visit among enrolled patients. We also estimated the prevalence, characteristics (QTc prolongation, absorption interactions, etc.), and severity of OACD-related potential DDIs. Lexicomp was used to assess potential DDIs and measure severity on a standardized scale where A signifies no interaction, B no action needed, C monitor therapy, D modify regimen, and X, avoid combination. In addition, we assessed the prevalence of medication list inaccuracies, polypharmacy, patient satisfaction, and patient perception of acceptability, appropriateness, and feasibility of the intervention. Results: Forty-three of the 58 eligible enrolled patients (74%) completed a pharmacist-led video visit, exceeding our feasibility definition. Among those 58 patients, mean age was 71 years (SD 12.3), and 26 patients (60%) were male. Twenty-two patients were non-Hispanic white (51%). Thirty-four patients (63%) were insured by Medicare, Medicaid, or both. The median number of standing prescriptions per patient was 9 (range: 4 – 21), and 98% of patients had at least 5 listed. The median number of medication list errors was 2 (range: 0 – 16), with at least 1 error for 76% and >1 error for 52% of patients. Pharmacists identified potential DDIs in 20 cases (47%). These included change in drug metabolism (9), QTc prolongation (1), elimination (1), and absorption (3). Interactions were classified as either category C (15) or D (5), requiring close monitoring or a change in treatment, respectively. All patients were somewhat or very satisfied with the visit, and agreed or completely agreed that the intervention was acceptable, appropriate, and feasible. Conclusions: Polypharmacy, medication list errors, and potential DDIs are prevalent among patients initiating OACDs. Our study suggests that a one-time remote 30-minute pharmacist-led video consultation is feasible and can effectively identify and address potential OACD-related DDIs, which may decrease medication complexity and improve adherence in this population.

Updates on the Interactions of Herbs Constituents with Cytochrome P450 Drug Metabolizing Enzymes

Abstract: Cytochrome P450 enzymes are the main drug-metabolizing enzyme, and their activity is influenced by numerous factors, including several plants’ constituents. Herbal products mediated induction or inhibition of cytochrome P450 leads to a change in drug metabolism and consequently, drug bioavailability, safety, therapeutic efficacy, and herb-drug interaction. Since herbal preparations are commonly used either alone or concomitantly with conventional drugs, understanding the interactions of plant constituents with cytochrome P450 is crucial. Therefore, this review highlighted plants with significant inhibition, induction, or modulatory /contradictory effects on human and animal cytochrome P450 enzymes. An extensive literature search was conducted on PubMed, ScienceDirect, and Google Scholar databases to identify relevant literature. About sixty medicinal plants with significant interaction with cytochrome P450 isoforms were summarized with their common uses and affected cytochrome P450 enzyme isoforms. Besides, representative examples of plant constituents and other factors contributing to plant-induced cytochrome P450 modulation and possible herb-drug interactions were also discussed in this review.

Mechanistic, functional and clinical aspects of pro-inflammatory cytokine mediated regulation of ADME gene expression in 3D human liver spheroids.

During systemic inflammation, pro-inflammatory cytokines alter metabolism and transport of drugs affecting the clincal outcome. We used an in vivo like human 3D liver spheroid model to study the effects and mechanisms of pro-inflammatory cytokines on the expression of nine different genes encoding enzymes responsible for the metabolism of > 90% of clinically used drugs. Treatment of spheroids with pathophysiologically relevant concentrations of IL-1β, IL-6 or TNFα resulted in a pronounced decrease in mRNA expression of CYP3A4 and UGT2B10 within 5 h. The reduction of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 mRNA expression was less pronounced, whereas the pro-inflammatory cytokines caused increased CYP2E1 and UGT1A3 mRNA expression. The cytokines did not influence expression of key nuclear proteins, nor the activities of specific kinases involved in the regulation of genes encoding drug metabolizing enzymes. However, ruxolitinib, a JAK1/2 inhibitor, inhibited the IL-6 dependent increase in CYP2E1 and the decrease in CYP3A4 and UGT2B10 mRNA expression. We evaluated the effect of TNFα in hepatocytes in 2D plates and found a rapid decrease in DME mRNA both in the absence or presence of the cytokines. Taken together, these data suggest that pro-inflammatory cytokines regulate multiple gene- and cytokine-specific events seen in in vivo and in 3D but not in 2D liver models. We propose that the 3D spheroid system is suitable for the prediction of drug metabolism under conditions of inflammation and constitutes a versatile system for short- and long-term pre-clinical and mechanistic studies of cytokine-induced changes in drug metabolism.

Metabolites from scutellarin alleviating deferoxamine-induced hypoxia injury in BV2 cells cultured on microfluidic chip combined with a mass spectrometer

The changes of metabolites of tricarboxylic acid (TCA) cycle in cells under hypoxia play a key role in drug screening. In order to dynamically monitor the drug metabolism changes of Scutellarin in the hypoxia environment induced by deferoxamine (DFO), a microfluidic-chip mass spectrometry method was used to study the real-time monitoring of drug metabolism changes under hypoxia conditions. This system has six drug-loading units, cell culture chamber, metabolite collection, filtration, HPLC separation and mass spectrometer. The cells in each microchannel were incubated with continuous flow of culture medium, metabolites will be collected by the fixed card slot, automatic sampling needle will be precise positioned and sampled. Through this new system combined with molecular biological methods, the changes of metabolites in TCA cycle of BV2 cells and drug metabolism of Scutellarin can be determined in real-time. In general, we illustrated a new mechanism of Scutellarin for reducing BV2 cell hypoxia injury and presented a novel analysis strategy that opened a way for real-time online monitoring of the energy metabolic mechanism of the effect of drugs on cells and further provided a superior strategy to screen natural drug candidates for hypoxia-related brain disease treatment.

339 Dupilumab 16-week efficacy and safety are robust and consistent in adults over 60 years of age with moderate-to-severe atopic dermatitis

Abstract Atopic dermatitis (AD) may be more common than previously thought in adults aged ≥60 years, a population underrepresented in clinical trials. Rigorous demonstration of efficacy and safety in older adults is clinically important due to distinct disease presentations in this group, age-related immune shifts, changes in drug metabolism and risks associated with a heightened burden of medical comorbidities and polypharmacy. Treatment options providing efficacy with acceptable safety profiles are of particular importance. Here, we report the efficacy and safety of dupilumab for the treatment of moderate-to-severe AD in patients aged ≥60 years. Data were pooled from four randomized, placebo-controlled dupilumab trials in patients with moderate-to-severe AD (LIBERTY AD SOLO 1 & 2 [NCT02277743, NCT02277769], LIBERTY AD CAFÉ [NCT02755649] and LIBERTY AD CHRONOS [NCT02260986]). Patients aged ≥60 years (N = 183) received dupilumab 300 mg weekly (qw), every 2 weeks (q2w) or a placebo. Topical corticosteroids (TCSs) were permitted in LIBERTY AD CAFÉ and LIBERTY AD CHRONOS. Reported efficacy measures include the percentage of patients achieving a 75% reduction in Eczema Area and Severity Index (EASI-75), mean change in Peak Pruritus Numerical Rating Scale (PP-NRS) scores, and mean change in Dermatology Life Quality Index (DLQI). Safety data are also presented. Among patients aged ≥60 years, significant increases in EASI-75 responses were observed in patients treated with dupilumab 300 mg qw (61.6%) and 300 mg q2w (63.0%) vs. placebo (14.3%; P < 0.0001 for both) at week 16. Least squares (LS) mean change (± standard error [SE]) in PP-NRS scores was significantly greater in patients treated with dupilumab 300 mg qw (−1.6 [0.2]) and 300 mg q2w (−1.7 [0.3]) vs. placebo (−0.9 [0.3]; P < 0.05 for both) at week 2. Improvements continued to week 16 in patients treated with dupilumab 300 mg qw (−4.0 [0.3]) and 300 mg q2w (−3.8 [0.3]) vs. placebo (−1.7 [0.3]; P < 0.0001 for both). Similarly, significant improvement (LS mean change [±SE]) in DLQI was seen in patients treated with dupilumab 300 mg qw (−5.0 [0.6]) and 300 mg q2w (−6.0 [0.7]) vs. placebo (−2.8 [0.6]; P < 0.01 vs. qw and P < 0.001 vs. q2w) at week 2; improvements continued to week 16 in patients treated with dupilumab 300 mg qw (−8.0 [0.6]) and 300 mg q2w (−9.65 [0.7]) vs. placebo (−3.3 [0.7]; P < 0.0001 for both). 52 (72.2%) patients in the 300 mg qw treatment group, 32 (58.2%) patients in the 300 mg q2w treatment group, and 40 (71.4%) patients in the placebo group experienced ≥1 TEAE. The two most common treatment-emergent adverse events (TEAEs) were injection-site reactions (13.9%) and nasopharyngitis (9.7%) during 300 mg qw dupilumab treatment; dermatitis atopic (20.0%) and nasopharyngitis (5.5%) during 300 mg q2w dupilumab treatment; and dermatitis atopic (30.4%) and upper respiratory tract infection (7.1%) during placebo treatment. 3 (4.2%) patients during 300 mg qw dupilumab treatment and 2 (3.6%) patients during 300 mg q2w dupilumab treatment discontinued treatment permanently as a result of TEAEs. Dupilumab efficacy and safety profiles in patients aged ≥60 years were generally consistent with that seen in patients aged <60 years with atopic dermatitis, and have been previously reported. Dupilumab, with or without TCS, improves AD signs, symptoms and quality of life with a consistent and acceptable safety profile in patients aged ≥60 years with moderate-to-severe AD.

Improving Drug Therapy for Pediatric Patients: Unfinished History of Pediatric Drug Development.

Improving Drug Therapy for Pediatric Patients: Unfinished History of Pediatric Drug Development.

Sensitive liquid chromatography/tandem mass spectrometry method for the simultaneous determination of seventeen beta blockers

In recent years, examples of drugs responsible for acute drug intoxication in elderly people include benzodiazepines, phenobarbital, digitalis preparations, phenytoin, beta blockers or calcium antagonists, and antidepressants in Japan. Due to the diversity of underlying diseases, the reasons for this include increasing number of prescription medicines due to regular oral medicines themselves interacting, and age-related changes in drug metabolism. Beta blockers for clinical use are employed in the management of a range of disorders, including hypertension, heart failure, arrhythmias, migraine headache and tremor. Beta blockers are prescribed widely and also have a high frequency of accidental ingestion by the elderly people. Cardiovascular drugs (beta blockers) present more serious symptoms of intoxication than the underlying diseases themselves. The aim of this study is to develop and validate a sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) with ESI method for the simultaneous determination of seventeen beta blockers (atenolol, carteolol, nadolol, pindolol, timolol, acebutolol, arotinolol, metoprolol, esmolol, celiprolol, labetalol, bisoprolol, propranolol, alprenolol, betaxolol, bevantolol and carvedilol). The extractions of beta blockers in human serum were performed by solid-phase extraction method using Oasis® PRiME HLB column (Waters). LC-MS/MS experiments were performed with a HPLC system, which consisted of Shimadzu LC-20AD pumps, a SIL-20AC autosampler and the 4000 QTRAP mass spectrometer (AB SCIEX). The chromatographic separation was performed on a Mightysil-RP-18 MS column (150 × 2.0-mm i.d., 5 μm). For the gradient elution, two solvents were used: (A) 10 mM acetic ammonium buffer and (B) acetonitrile. The flow rate was 0.20 mL/min and the column and autosampler were maintained at 37 and 4˚C, respectively. The settings of the turbo ion-spray were as follows; curtain gas, N2:40 psi, collision gas, N2:4 psi, collision energy: 27∼41 V, ion-spray voltage: 5500 V, ionization mode: ESI positive, source temperature: 600˚C. Separation and sensitivity for the detection of seventeen beta blockers by LC-MS/MS were sufficient and the precursor [M + H]+ ion was detected in the mass spectrum for each drug. This method had a chromatographic total run time of 15 min. The calibration curves were linear over the concentration range of 20–400 ng/mL for seventeen beta blockers (r = 0.9686∼0.9997). The extraction yields of human serum sample with Oasis® PRiME HLB column were ranged from 66.1 to 93.5%, the precision within 0.07 CV values were acceptable of this method. But the extraction yields of bevantlol (37.5%) and carvedilol (26.2%) were low. Currently, we are experimenting to improve the extraction yields of bevantolol and carvedilol. Phyo Lwin EM, et al (2017, Bioanalysis.) developed a method for the determination of atenolol in human plasma and milk sample by LC-MS/MS. The limits of detection (LOD) and quantification (LOQ) were in the range 1.0 ng/mL and 5.0 ng/mL for atenolol. Our LC-MS/MS with ESI method was able to measure compounds at approximately the same concentrations as the analytical methods of Phyo Lwin EM, et al. In our experiments, LOD and LOQ in the range 0.0034–1.6 ng/mL and were 20 ng/mL for seventeen beta blockers. The presently established method is very useful for simultaneous measurements of beta blockers in human serum by LC-MS/MS in clinical and forensic investigations.

Treatment and care of women with epilepsy before, during, and after pregnancy: a practical guide.

Women with epilepsy (WWE) wishing for a child represent a highly relevant subgroup of epilepsy patients. The treating epileptologist needs to delineate the epilepsy syndrome and choose the appropriate anti-seizure medication (ASM) considering the main goal of seizure freedom, teratogenic risks, changes in drug metabolism during pregnancy and postpartum, demanding for up-titration during and down-titration after pregnancy. Folic acid or vitamin K supplements and breastfeeding are also discussed in this review. Lamotrigine and levetiracetam have the lowest teratogenic potential. Data on teratogenic risks are also favorable for oxcarbazepine, whereas topiramate tends to have an unfavorable profile. Valproate needs special emphasis. It is most effective in generalized seizures but should be avoided whenever possible due to its teratogenic effects and the negative impact on neuropsychological development of in utero-exposed children. Valproate still has its justification in patients not achieving seizure freedom with other ASMs or if a woman decides to or cannot become pregnant for any reason. When valproate is the most appropriate treatment option, the patient and caregiver must be fully informed of the risks associated with its use during pregnancies. Folate supplementation is recommended to reduce the risk of major congenital malformations. However, there is insufficient information to address the optimal dose and it is unclear whether higher doses offer greater protection. There is currently no general recommendation for a peripartum vitamin K prophylaxis. During pregnancy most ASMs (e.g. lamotrigine, oxcarbazepine, and levetiracetam) need to be increased to compensate for the decline in serum levels; exceptions are valproate and carbamazepine. Postpartum, baseline levels are reached relatively fast, and down-titration is performed empirically. Many ASMs in monotherapy are (moderately) safe for breastfeeding and women should be encouraged to do so. This review provides a practically oriented overview of the complex management of WWE before, during, and after pregnancy.

The association of CD4 lymphocyte count with drug hypersensitivity reaction to highly active antiretroviral therapy, trimethoprim sulfamethoxazole, and antitubercular agents in human immunodeficiency virus patients.

BackgroundThe introduction of highly active antiretroviral therapy (HAART) and antibiotic regimens for the treatment of human immunodeficiency virus (HIV) and its concomitant opportunistic infections, respectively, significantly improve the morbidity and mortality of the infected patients. However, these drugs commonly cause drug hypersensitivity reactions (DHRs) in patients with acquired immunodeficiency syndrome. The reason proposed are multifactorial, which includes immune hyperactivation, changes in drug metabolism, patient cytokine profiles, oxidative stress, genetic predisposition, and the principal target in HIV patients, the CD4+ lymphocytes.ObjectiveThis study determined the association of CD4 count and DHRs to first-line HAART, trimethoprim sulfamethoxazole, and antitubercular agents among HIV patients.MethodsThis is a retrospective analytical study. Review of charts were done. The demographic and clinical profile used a descriptive statistics such as mean and standard deviation for quantitative data and frequency and percent for categorical data. Chi-square and Fisher exact tests were used to measure the degree of the relationship of CD4 count and DHRs.ResultsA total of 337 eligible patients were included. There was a 25% incidence of hypersensitivity reactions. However, the prevalence of DHRs across the different CD4 groups was not statistically significant (p = 0.167). Likewise, the study found no significant association between the CD4 count and DHRs to first-line HAART, trimethoprim sulfamethoxazole, and antitubercular agents (p = 0.311). The most common DHR was morbilliform rash, and nevirapine was the most reported antiretroviral drug causing DHR.ConclusionThere was no association in the CD4 count and DHRs to first-line HAART, trimethoprim sulfamethoxazole, and antitubercular agents. Hence, regardless of the baseline CD4 lymphocyte count, the physician should be vigilant in monitoring hypersensitivity reactions. Patient education on common DHRs is very important upon diagnosis of HIV and/or initiation of treatment.

Particular Patterns of the Influence of the Physiology of Normal Pregnancy on the Pharmacokinetics of Drugs in the Liver

Pregnant women are the most "untouchable" group of people in relation to pharmacological research due to ethical and legal aspects, as well as concerns for the health and integrity of the fetus. And that is why pregnant women practically do not participate in clinical, pharmacodynamic, or pharmacokinetic testing. The mechanisms of teratogenesis are unpredictable, and in this case mutations can occur regardless of the duration of pregnancy and at any level. In women during pregnancy, the activity of liver enzyme systems involved in drug metabolism changes completely, which affects their clearance. This should be taken into account when selecting drugs and dosages for the treatment of various diseases. Our study showed that during pregnancy, a significant decrease in the intrinsic hepatic clearance of the CYP1A2 substrate is enhanced by a decrease in the binding of theophylline to plasma proteins and an increase in the glomerular filtration rate.