Pharmacodynamic Differences Research Articles

How does pain management differ - the basics of analgesia in pediatric patients compared to the adult population

Pain management is a key component of medical care that shows significant differences in pharmacodynamics, epidemiology or psychological approaches between pediatric and adult patient populations. An analgesic drug is an agent used to treat pain. It is often inadequate and ineffective in pediatric patients - the younger the children, the less likely they are to receive adequate analgesia. Optimizing pain management in both populations requires continuous improvement in clinical practice and education of medical personnel and patients on pharmacological and non-pharmacological approaches. This article discusses the characteristics of analgesic use in children and adults and non-pharmacological approaches to pain management. Objectives: The purpose of our study is to evaluate the methods of analgesia used in the pediatric population and in adult patients and the differences associated with age group membership. Materials and Methods: The literature review was performed using Internet research paper databases (PubMed, Google Scholar, Medline), using 28 articles available in English and Polish from 1983-2024. Results: Analgesia in children has its own specific characteristics that differ from analgesia in adults. These include differences in pain sensitivity, age dependence, pain rating scale, psychological aspects, choice of analgesic drug or drug dosage. Conclusion: Improving the quality of analgesia in children requires both pharmacological support and the use of non-pharmacological methods, education of doctors and parents, and emotional support.

Effectiveness of ceftazidime-avibactam versus ceftolozane-tazobactam for multidrug-resistant Pseudomonas aeruginosa infections in the USA (CACTUS): a multicentre, retrospective, observational study.

Ceftolozane-tazobactam and ceftazidime-avibactam are preferred treatment options for multidrug-resistant Pseudomonas aeruginosa infections; however, real-world comparative effectiveness studies are scarce. Pharmacokinetic and pharmacodynamic differences between the agents might affect clinical response rates. We aimed to compare the effectiveness of ceftolozane-tazobactam and ceftazidime-avibactam for treatment of invasive multidrug-resistant P aeruginosa infections. This multicentre, retrospective, observational study was conducted at 28 hospitals in the USA between Jan 1, 2016, and Dec 31, 2023. Eligible patients were adults (age ≥18 years old) with microbiologically confirmed multidrug-resistant P aeruginosa pneumonia or bacteraemia treated with ceftolozane-tazobactam or ceftazidime-avibactam for more than 48 h. Patients were matched (1:1) by study site, severity of illness, time to treatment initiation (≤72 h or >72 h), and infection type. The primary outcome was clinical success at day 30, which was defined as survival, resolution of signs and symptoms of infection with the intended treatment course, and the absence of recurrent infection due to P aeruginosa. Secondary outcomes included all-cause mortality and development of resistance to study drug. 420 eligible patients were included (210 in each treatment group), of whom 350 (83%) had pneumonia and 70 (17%) had bacteraemia. Baseline demographics, comorbidities, and severity of illness indicators were similar between groups. On treatment initiation, 336 (80%) patients were in the intensive care unit, 296 (70%) were receiving mechanical ventilation, and 168 (40%) required vasopressor support. Clinical success was observed in 128 (61%) of 210 patients treated with ceftolozane-tazobactam and 109 (52%) of 210 patients treated with ceftazidime-avibactam. By conditional logistic regression analysis, the adjusted odds ratio (aOR) of success after treatment with ceftolozane-tazobactam compared with ceftazidime-avibactam was 2·07 (95% CI 1·16-3·70). For patients with pneumonia, clinical success was observed in 110 (63%) of 175 patients in the ceftolozane-tazobactam group and 89 (51%) of 175 patients in the ceftazidime-avibactam group (aOR 2·34 [95% CI 1·22-4·47]). Among patients with bacteraemia, rates of clinical success were 51% (18 of 35 patients) for patients treated with ceftolozane-tazobactam and 57% (20 of 35 patients) for those treated with ceftazidime-avibactam (0·76 [0·23-2·57]). There were no significant differences between groups in 30-day or 90-day mortality. Among patients whose baseline isolates were tested for susceptibility, resistance developed in 22% (38 of 173) of patients treated with ceftolozane-tazobactam and 23% (40 of 177) of patients treated with ceftazidime-avibactam. Treatment with ceftolozane-tazobactam resulted in higher rates of clinical success compared with ceftazidime-avibactam for invasive infections due to multidrug-resistant P aeruginosa. Differences were driven by improved response rates for patients with pneumonia who were treated with ceftolozane-tazobactam. There were no significant differences between study groups with respect to all-cause mortality; treatment-emergent resistance was common with both agents. Merck Sharp & Dohme.

Various crystalline forms of realgar exhibit differentiated anti-abscess and anticancer effects based on a PXRD analysis and biological evaluation

Ethnopharmacological relevanceRealgar is a mineral medicine with a long history that can be used externally or internally. It is often used to treat skin diseases and leukemia in clinical practice. Realgar exhibits a polycrystalline phenomenon, and it remains unknown whether there is a difference in the efficacies of the different realgar crystalline forms. PurposeThe aim of this study is to investigate the pharmacodynamic differences of the different realgar crystalline forms (α-As4S4 and β-As4S4) using in vivo and in vitro experiments. Material and methodsThe in realgar crystalline patterns were initially identified using a powder x-ray diffractometer (PXRD). The antimicrobial activities of α-As4S4 and β-As4S4 were then assessed in vitro to elucidate their effectiveness against bacteria. Transdermal absorption and pharmacokinetic experiments were used to investigate the variances in the bioavailabilities between the in vitro and in vivo conditions. The effects of α-As4S4 and β-As4S4 for skin abscess healing were studied in mice using a subcutaneous injection of Staphylococcus aureus (S. aureus). HL-60 cells were exposed to a serum that contained different crystalline forms of realgar to evaluate the potential differences in the therapeutic effects of α-As4S4 and β-As4S4 on leukemia. ResultsRealgar is composed of α-As4S4 and β-As4S4 crystalline forms. The soluble arsenic content in α-As4S4 generally exceeded that of β-As4S4, and the antimicrobial activity showed a positive correlation with the soluble arsenic content. α-As4S4 demonstrated a higher in vivo and in vitro bioavailability and a faster elimination rate in vivo compared to β-As4S4. The pharmacodynamic experimental investigations showed that α-As4S4 exhibited a superior healing effect on subcutaneous abscesses. Furthermore, serum pharmacology experiments revealed that α-As4S4 induced significantly higher membrane damage and apoptosis in HL-60 cells compared to β-As4S4. ConclusionThe different realgar crystalline forms had distinct pharmacodynamics. α-As4S4 demonstrated higher bioavailability in vitro and in vivo and superior effects on skin abscess healing compared to β-As4S4. It also possessed anti-leukemia properties. It is the first time to report the differences in the efficacy between two crystalline forms of realgar, which is helpful to improve the knowledge of the real chemical substances for realgar.

JAK inhibitors: an evidence-based choice of the most appropriate molecule.

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis.

The effect of concurrent clopidogrel and omeprazole administration on clopidogrel metabolism and platelet function in healthy cats.

Some studies in humans show that the concurrent use of clopidogrel and omeprazole decreases plasma clopidogrel active metabolite (CAM) concentrations and clopidogrel antiplatelet effects. Whether this drug interaction occurs in cats is unknown. We hypothesized that administration of clopidogrel with omeprazole would decrease plasma CAM concentrations and decrease clopidogrel antiplatelet effects in healthy cats. Ten domestic cats. In this 2-sequence, 2-period, 2-treatment randomized crossover study, healthy cats were randomly assigned to receive clopidogrel only (18.75 mg PO q24h) or clopidogrel with omeprazole (1 mg/kg PO q12h) for 10 days, followed by a 2-week washout period, and then the opposite treatment for another 10 days. Blood was collected by jugular venipuncture on days 0, 5, and 10. Plasma CAM concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Platelet function was evaluated using Plateletworks, Multiplate Analyzer, and Platelet Function Analyzer-100 (PFA-100). Multiplate Analyzer and PFA-100 detected no difference in platelet function between days or treatment groups. Plateletworks detected a significant difference (P < .001) in platelet function from day 0 to 5 and day 0 to 10 in both treatment groups but no difference between treatment groups. Plasma CAM concentrations were significantly lower on day 10 (P < .02) in cats receiving both medications versus clopidogrel only. Concurrent omeprazole and clopidogrel administration was associated with altered pharmacokinetics on day 10, but no difference in pharmacodynamics between the 2 treatment groups. The short-term use of clopidogrel and omeprazole does not seem to alter platelet function significantly.

Identifying Vulnerabilities to NSAID Adverse Events in the U.S. Population: An Analysis of Preexisting Conditions and Sex.

Purpose: In 2005, the Food and Drug Administration (FDA) issued a decision memorandum regarding nonsteroidal anti-inflammatory drugs (NSAIDs). The memorandum recommended the withdrawal of certain NSAIDs due to potential cardiovascular adverse effects. It highlighted the issue of cardiovascular risk associated with NSAIDs as a class. The NSAID medication guide includes a wide range of adverse drug reactions (ADRs), such as increased blood pressure, liver failure, allergic reactions, heart attack, and intestinal bleeding. Although both sexes have an increased risk of ADRs with NSAID use, females have a greater risk than males due to differences in pharmacodynamics and higher medication concentrations (mg/kg). In particular, females with high blood pressure, coronary heart, kidney, and liver disease are at an additional risk of harm from NSAID ADRs. This study quantifies sex-specific differences and other factors associated with prescription NSAID use. Method: The data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES), a complex survey conducted by the Centers for Disease Control and Prevention (CDC) in two-year cycles. A survey-weighted logistic regression model was utilized to investigate potential sex differences with prescription NSAIDs in the context of other factors, including kidney disease, hypertension, liver disease, insurance status, coronary heart disease, and age, within the 2011-2018 NHANES survey data. Results: Females reported a slightly higher percentage of high blood pressure and kidney disease than males, while males reported a slightly higher percentage of coronary heart and liver disease than females. Last, the model indicated that females were 58% more likely to have used a prescription NSAID than males. Conclusion: The results confirm that women and people with medical conditions, who would potentially suffer greater harm from NSAID ADRs, are more likely to use a prescription NSAID than individuals without these conditions.

Methods of correction of hyperprolactinemia induced by antipsychotics: current state of the problem and development prospects

Hyperprolactinemia is one of the common undesirable phenomena of antipsychotic therapy, as it is associated with a number of mental and somatic complications. To date, there are several strategies for the correction of antipsychotics induced hyperprolactinemia, the most evidential basis of which has an addition to the current treatment of partial dopamine agonist — aripiprazole.Other drugs in this group, cariprazine and brexpiprazole, due to a similar mechanism of action with aripiprazole, belong to prolactin-saving drugs. However, their differences in pharmacodynamics may determine features in prolactin effects and attract attention for further study of their prolactin-saving activity.

The Intoxication Equivalency of 11-Hydroxy-Δ9-Tetrahydrocannabinol Relative to Δ9-Tetrahydrocannabinol.

Δ9-Tetrahydrocannabinol (THC) is a psychoactive phytocannabinoid found in the Cannabis sativa plant. THC is primarily metabolized into 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), which may themselves be psychoactive. There is very little research-based evidence concerning the pharmacokinetics and pharmacodynamics of 11-OH-THC as an individual compound. Male C57BL/6 mice were treated with THC or 11-OH-THC via intraperitoneal injection, tail vein intravenous injection, or oral gavage, and whole-blood compound levels were measured to determine pharmacokinetic parameters [Cmax, time to Cmax (Tmax), elimination half-life, area under the curve, apparent volume of distribution, systemic clearance, terminal rate constant, and absolute bioavailability] while also monitoring changes in catalepsy, body temperature, and nociception. 11-OH-THC achieved a Tmax at 30 minutes for all routes of administration. The maximum concentration at 30 minutes was not different between intravenous and intraperitoneal routes, but the oral gavage Cmax was significantly lower. THC had a 10-minute time to the maximum concentration, which was the first blood collection time point, for intravenous and intraperitoneal and 60 minutes for oral gavage, with a lower Cmax for intraperitoneal and oral gavage compared with intravenous. When accounting for circulating compound levels and ED50 responses, these data suggest that 11-OH-THC was 153% as active as THC in the tail-flick test of nociception and 78% as active as THC for catalepsy. Therefore, 11-OH-THC displayed equal or greater activity than the parent compound THC, even when accounting for pharmacokinetic differences. Thus, the THC metabolite 11-OH-THC likely plays a critical role in the bioactivity of cannabis; understanding its activity when administered directly will aid in the interpretation of future animal and human studies. SIGNIFICANCE STATEMENT: This study establishes that the primary metabolite of THC, 11-OH-THC, displays equal or greater activity than THC in a mouse model of cannabinoid activity when directly administered and even when accounting for route of administration, sex, pharmacokinetic, and pharmacodynamic differences. These data provide critical insight into the bioactivity of THC metabolites that will inform the interpretation of future in vivo cannabinoid research and represent a model for how THC consumption and metabolism may affect cannabis use in humans.

Differential metabolite analysis of the pharmacodynamic differences between different ratios of Dahuang ()-Taoren () herb pair.

To explore the material basis of the difference of efficacy of Dahuang (Radix Et Rhizoma Rhei Palmati)-Taoren (Semen Persicae) (DT) drugs with different proportions. Samples of different ratios of Dahuang (Radix et Rhizoma Rhei Palnati, DH) to Taoren (Semen Persicae, TR) (Group A 1:1, B 2:3, C 3:2) were analyzed based on gas chromatography time-of-flight mass spectrometry untargeted metabolomics technique. A total of 240 primary metabolites were detected. Forty-one differential metabolites involved nine differential metabolic pathways, of which four were closely related to the efficacy of DT in the treatment of heat and blood stasis syndrome. These pathways included the biosynthesis of amino acid (phenylalanine tyrosine and tryptophan), flavonoids, unsaturated fatty acids, and the glycolysis/glycogenesis pathway. There are significant differences in the efficacy of different ratios of DT drugs, and their optimal ratio for the treatment of heat and blood stasis syndrome should be 1:1.

Italian Association of Hospital Cardiologists Position Paper 'Gender discrepancy: time to implement gender-based clinical management'.

It has been well assessed that women have been widely under-represented in cardiovascular clinical trials. Moreover, a significant discrepancy in pharmacological and interventional strategies has been reported. Therefore, poor outcomes and more significant mortality have been shown in many diseases. Pharmacokinetic and pharmacodynamic differences in drug metabolism have also been described so that effectiveness could be different according to sex. However, awareness about the gender gap remains too scarce. Consequently, gender-specific guidelines are lacking, and the need for a sex-specific approach has become more evident in the last few years. This paper aims to evaluate different therapeutic approaches to managing the most common women's diseases.

Sex differences in the prognostic role of achieving target doses of heart failure medications: Data from the Swedish Heart Failure Registry.

Guidelines recommend target doses (TD) of heart failure (HF) with reduced ejection fraction (HFrEF) medications regardless of sex. Differences in pharmacokinetics and pharmacodynamics may explain heterogeneity in treatment response, adverse reactions, and tolerability issues across sexes. The aim of this study was to explore sex-based differences in the association between TD achievement and mortality/morbidity in HFrEF. Patients with HFrEF and HF duration ≥6 months registered in the Swedish HF Registry between May 2000 and December 2020 (follow-up until December 2021) were analysed. Treatments of interest were renin-angiotensin system inhibitors (RASI) or angiotensin receptor-neprilysin inhibitors (ARNI), and beta-blockers. Multivariable Cox regression models were performed to explore the risk of cardiovascular mortality or hospitalization for HF across dose categories in females versus males. A total of 17 912 patients were analysed (median age 77.0 years, interquartile range [IQR] 70.0-83.0), 29% were female. Over a median follow-up of 1.33 years (IQR 0.29-3.22), for RASI/ARNI there was no significant difference in outcome for females achieving 50-99% versus 100% of TD (hazard ratio 0.92, 95% confidence interval 0.83-1.03), whereas males showed a gradual lowering in risk together with the achievement of higher % of TD (p-interaction = 0.030). For beta-blockers the achievement of TD was associated with the lowest risk of outcome regardless of sex. Our findings suggest that females and males might differently benefit from the same dose of RASI/ARNI, and do represent a general call for randomized controlled trials to consider sex-specific up-titration schemes when testing HFrEF treatments in need of up-titration.

Diagnosis and therapy of patients with asthma in Germany. Results of the care study RELEVANT

Diagnostic and therapeutic options for asthma have improved with asthma control and remission being of central importance. The RELEVANT study aimed for a nationwide snapshot of current asthma diagnosis and treatment in general practice and specialty care for identification of further aspects for optimization. RELEVANT is a nationwide cross-sectional study using a structured questionnaire. This comprised 14 questions on asthma-related topics covering diagnostics and therapy. Participants were general practitioners/internal medicine specialists and pulmonologists. A total of 1,558 persons took part in the survey. Regarding relevant specific diagnostic procedures for asthma, GPs/internists almost exclusively mentioned pulse oximetry. Among the pulmonologists, fractional exhaled nitric oxide (FeNO) measurement was mentioned, among others. FeNO and blood eosinophils were only mentioned by the pulmonologists as diagnostic and treatment-relevant markers. A total of more than 60% of the GPs/internists surveyed stated that only around 25% or fewer of their patients would voluntarily report restrictions in their everyday lives. Regarding drug treatment, the majority stated that they recognized differences between various ICS/LABA combination therapies. The results indicate a need for optimization, particularly regarding asthma control. This involves both a better assessment by patients' everyday life restrictions and modern ways of assessing asthma control in cooperation between GPs/internal medicine specialists and pulmonologists. One fifth of respondents do not see any differences between various ICS/LABA combinations in daily practice, although there are pharmacodynamic and pharmacokinetic differences.

Liposomal Bupivacaine for Peripheral Nerve Blockade: A Randomized, Controlled, Crossover, Triple-blinded Pharmacodynamic Study in Volunteers.

Little is known about the pharmacodynamic characteristics of liposomal bupivacaine. Hypothesizing that they would not identify pharmacodynamic differences from plain bupivacaine during the initial period after administration, but would find better long-term pharmacodynamic characteristics, the authors designed a randomized, controlled, triple-blinded, single-center study in volunteers. Volunteers aged 18 to 55 yr (body mass index, 18 to 35 kg/m2) received two ulnar nerve blocks under ultrasound guidance. Using a crossover design with a washout phase of 36 days or more, one block was performed with liposomal and one with plain bupivacaine. Which came first was determined by randomization. Sensory data were collected by pinprick testing and motor data by thumb adduction, either way in comparison with the contralateral arm. Endpoints included success, time to onset, and duration of blockade. Residual efficacy was assessed by the volunteers keeping a diary. Statistical analysis included Wilcoxon signed-rank and exact McNemar's tests, as well as a generalized estimation equation model. Successful sensory blockade was noted in 8 of 25 volunteers (32%) after liposomal and in 25 of 25 (100%) after plain bupivacaine (P < 0.0001). Significant differences emerged for time to onset, defined as 0% response to pinpricking in four of five hypothenar supply areas (P < 0.0001), and for time from onset to 80% or 20% in one of five areas (P < 0.001; P < 0.001). Carryover effects due to the randomized sequencing were unlikely (estimate, -0.6286; sequence effect, 0.8772; P = 0.474). Self-assessment greater than 3.5 days did reveal, for liposomal bupivacaine only, intermittent but unpredictable episodes of residual sensory blockade. The results show that liposomal bupivacaine is not a suitable "sole" drug for intraoperative regional anesthesia. Findings of its limited long-term efficacy add to existing evidence that a moderate effect, at best, should be expected on postoperative pain therapy.

Pharmacodynamic characteristics, safety profile, and interactions of CDK4/6 inhibitors (CDK4/6i) in HR+/HER2– advanced/metastatic breast cancer

Abstract Targeted therapies such as cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) have improved the prognosis of hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+)/(HER2–) advanced/metastatic breast cancer (a/mBC) by combating the resistance observed with traditional endocrine therapy. Currently, palbociclib, ribociclib, and abemaciclib are the three medicinal products authorized by the European Medicines Agency and the Food and Drug Administration. In addition to their overall similarities, related to their primary molecular mechanism of action through CDK4/6 inhibition, they also exhibit significant pharmacodynamic differences that affect their efficacy and safety profile, which may, through further research, help in understanding predicted toxicity, safety, and interactions and assist in adjusting dosing regimens in daily clinical practice. This review article will examine the pharmacodynamic profile of CDK4/6 inhibitors, their efficacy and safety in the treatment of HR+/HER2– a/mBC.

Sex-related similarities and differences in responses to heart failure therapies.

Although sex-related differences in the epidemiology, risk factors, clinical characteristics and outcomes of heart failure are well known, investigations in the past decade have shed light on an often overlooked aspect of heart failure: the influence of sex on treatment response. Sex-related differences in anatomy, physiology, pharmacokinetics, pharmacodynamics and psychosocial factors might influence the response to pharmacological agents, device therapy and cardiac rehabilitation in patients with heart failure. In this Review, we discuss the similarities between men and women in their response to heart failure therapies, as well as the sex-related differences in treatment benefits, dose-response relationships, and tolerability and safety of guideline-directed medical therapy, device therapy and cardiac rehabilitation. We provide insights into the unique challenges faced by men and women with heart failure, highlight potential avenues for tailored therapeutic approaches and call for sex-specific evaluation of treatment efficacy and safety in future research.

Tissue specific distribution of terpenoid biosynthesis in Sarcandra glabra based on transcriptome and metabolome analysis

The leaves and roots of Sarcandra glabra (thunb) nakai have different therapeutic effects in some clinical applications. In order to explore the tissue specific distribution differences of terpenoids in the leaves and roots of S. glabra, and to analyze the molecular mechanism of the formation of their pharmacodynamic quality differences. In this study, liquid chromatography-mass spectrometry (LC-MS) and Illumina HiSeqTM high-throughput sequencing techniques were respectively used to obtain the metabolome and transcriptome data of the leaves and roots of S. glabra. The metabolomics analysis showed that there were 50 differential terpenoids metabolites between the leaves and roots, including farnesylcysteine, d-glyceraldehyde 3-phosphate, and (R)-5-phosphomevalonate. The transcriptomics analysis indicated that there were 57 differentially expressed metabolic enzyme coding genes, including ACTC, HMGCR, MVK, DXS, and KS. Moreover, there were seven transcription factors, including MYB, C2H2, AP2/ERF-ERF, which were predicted to participate in regulating the differences in terpenoid synthesis and accumulation between the leaves and roots of S. glabra. qRT-PCR results demonstrated that the expression changes of eight randomly selected enzyme genes involved in terpene synthesis between the leaves and roots of S. glabra, which were consistent with the transcriptome sequencing results. This study will help to elucidate the molecular mechanisms underlying the clinical efficacy differences between the leaves and roots of S. glabra, and facilitate the extraction, utilization, and resource development of S. glabra.

Sex-biased gene expression and gene-regulatory networks of sex-biased adverse event drug targets and drug metabolism genes

BackgroundPrevious pharmacovigilance studies and a retroactive review of cancer clinical trial studies identified that women were more likely to experience drug adverse events (i.e., any unintended effects of medication), and men were more likely to experience adverse events that resulted in hospitalization or death. These sex-biased adverse events (SBAEs) are due to many factors not entirely understood, including differences in body mass, hormones, pharmacokinetics, and liver drug metabolism enzymes and transporters.MethodsWe first identified drugs associated with SBAEs from the FDA Adverse Event Reporting System (FAERS) database. Next, we evaluated sex-specific gene expression of the known drug targets and metabolism enzymes for those SBAE-associated drugs. We also constructed sex-specific tissue gene-regulatory networks to determine if these known drug targets and metabolism enzymes from the SBAE-associated drugs had sex-specific gene-regulatory network properties and predicted regulatory relationships.ResultsWe identified liver-specific gene-regulatory differences for drug metabolism genes between males and females, which could explain observed sex differences in pharmacokinetics and pharmacodynamics. In addition, we found that ~ 85% of SBAE-associated drug targets had sex-biased gene expression or were core genes of sex- and tissue-specific network communities, significantly higher than randomly selected drug targets. Lastly, we provide the sex-biased drug-adverse event pairs, drug targets, and drug metabolism enzymes as a resource for the research community.ConclusionsOverall, we provide evidence that many SBAEs are associated with drug targets and drug metabolism genes that are differentially expressed and regulated between males and females. These SBAE-associated drug metabolism enzymes and drug targets may be useful for future studies seeking to explain or predict SBAEs.

Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients.

While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment. To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting. Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach. Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p<0.001) and sunitinib (58.6%; p=0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035ng/mL [IQR 773-1377]; p<0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p=0.270; sunitinib: p=0.547; and regorafenib: p=0.784). Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.

Analysis of compatibility mechanism of shenxiong glucose injection after multiple dosing based on differences of PK-PD correlation and cytochrome P450 enzyme

Shenxiong glucose injection (SGI) containing a water extract from the roots of Danshen and Ligustrazine hydrochloride, is the main drug used for the prevention and treatment of acute myocardial ischemia (AMI) in China. Based on the characteristics of drug clinical applications, this study aims to uncover the compatibility mechanism of SGI by investigating pharmacokinetic (PK) and pharmacodynamic (PD) differences between Danshen glucose injection (DGI), Ligustrazine glucose injection (LGI) and SGI groups after multiple dosing during the pathological state from the perspective of metabolic enzymes. Compared to the LGI group, the absorption (Cmax) and exposure (AUC) of ligustrazine increased significantly, and the protein expression of CYP1A2, CYP2C11 and CYP3A2 in the SGI group decreased significantly. Furthermore, the PK and PD experimental data for Danshen and ligustrazine in AMI rats were fitted to obtain a PK-PD binding model with three components. PK-PD parameter analysis showed that in the SGI group the IC50 values of ligustrazine and danshensu on AST, CK-MB, cTn-I and the IC50 values of rosmarinic acid on AST and CK-MB were lower than the DGI or LGI group. It is speculated that Danshen inhibited CYP1A2, CYP2C11 and CYP3A2 mediating the metabolism of ligustrazine and decreased the expression of these three isozymes, which further affected the in vivo process of ligustrazine. Moreover, the combination of Danshen and ligustrazine could have better regulating effect on AST, CK-MB and cTn-I. This preliminary study has provided a scientific basis for understanding the compatibility mechanism of SGI from the viewpoint of the regulation of CYP enzymes in the PK-PD model.

Pharmacodynamic differences between racemic ibuprofen and dexibuprofen in murine preclinical study

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain, but their use is restricted by their adverse effects. In this study, the pharmacological profile of ibuprofen and dexibuprofen was evaluated using the murine acetic acid writhing test, and the participation of naltrexone, naltrindole, nor-binaltorphimine, L-NAME, risperidone, and tropisetron in the antinociceptive efficacy. Antinociception was assessed by dose–response curves to ibuprofen and dexibuprofen before and after the i.p. administration of 1,0 mg/kg of naltrexone, or naltrindole, or norbinaltorphimine, or 5 mg/kg of L-NAME, 0,5 mg/kg of risperidone, or tropisetron in the murine assay. Results are presented as means ± SEM and differences calculated by one-way ANOVA followed by Tukey's post-test. Ibuprofen and dexibuprofen produced a dose-dependent antinociceptive effect with different potency. After pretreatment of mice with naltrexone, naltrindole, nor-binaltorphimine, L-NAME, risperidone, or tropisetron, a significant increase in ibuprofen efficacy was obtained, however, no effect on dexibuprofen activity was obtained. Data demonstrate that ibuprofen and dexibuprofen induce effective antinociception in the acetic acid writhing test, either directly, through COX inhibition, or indirectly, through the modulatory effects of opioid or serotonin, or nitric oxide receptors. These actions are complex since the effects depending on the chemical structure of the NSAID. Thus, a racemic compound (ibuprofen) induces a significant increase in nociceptive efficacy. However, they have no effect on the dextrorotatory enantiomer (dexibuprofen).