Pharmacodynamic Factors Research Articles

Pharmacological Management of Sleep-Wake Disturbances in Delirium.

Delirium is a heterogeneous syndrome primarily characterized by fluctuations in attention and awareness. Sleep-wake disturbances are a common and significant feature of delirium and can manifest as circadian rhythm inversion, sleep fragmentation, and reduced rapid eye movement (REM) and slow-wave sleep. Some literature suggests that the relationship between sleep disruption and delirium is reciprocal wherein the two reinforce one another and may share an underlying etiology. As there are no FDA-approved medications for delirium or delirium-related sleep disturbances, management is primarily focused on addressing underlying medical concerns and promoting physiologic circadian patterns with non-pharmacological behavioral interventions. In practice, however, medications are often used, albeit with limited evidence to support their use. This literature review explores the pharmacology and pharmacokinetics of several medications with literature investigating their use in delirium: melatonin, ramelteon, dual orexin receptor antagonists (DORAs), and dexmedetomidine. Current evidence suggests a possible benefit of ramelteon or melatonin, dexmedetomidine for patients in the ICU setting, and DORAs as therapeutic options for the re-regulation of sleep-wake cycle disruption in delirium. We discuss pertinent pharmacokinetic and pharmacodynamic factors that may influence clinical decision-making regarding these interventions.

Research progress on effect evaluation and application status of acupoint drug delivery

Acupoint drug delivery is a traditional external therapy of traditional Chinese medicine(TCM). Guided by the meridian and collateral theory in TCM, it applies medications to the skin at acupoints, exerting a dual therapeutic effect by stimulating the acupoints and the conduction of meridians. Acupoint drug delivery is widely used in clinical practice. Different from traditional oral admi-nistration and injection, it absorbs medications through the skin, effectively avoiding the first-pass effect of drugs and the toxic side effects caused by injection. Acupoint selection and transdermal drug absorption are pivotal factors affecting the efficacy of acupoint drug delivery. Recent research on acupoint drug delivery mainly focuses on the evaluation of clinical efficacy, yet the systematic investigations on acupoint selection and pharmacodynamic factors are scarce. This study reviews the mechanism, efficacy evaluation and application status of acupoint drug delivery. It integrates the theory of TCM with modern medicine to explore the mechanism of acupoint drug delivery, evaluate its clinical efficacy, and assess the transdermal penetration in vivo and in vitro. The application status of acupoint drug delivery is also summarized, including the selection of acupoints, application dosage form, application time and the absorption of acupoints. This review aims to offer insights and references for the research, development and clinical application of acupoint drug delivery products.

Optimal use of β-lactams in neonates: machine learning-based clinical decision support system

BackgroundAccurate prediction of the optimal dose for β-lactam antibiotics in neonatal sepsis is challenging. We aimed to evaluate whether a reliable clinical decision support system (CDSS) based on machine learning (ML) can assist clinicians in making optimal dose selections. MethodsFive β-lactam antibiotics (amoxicillin, ceftazidime, cefotaxime, meropenem and latamoxef), commonly used to treat neonatal sepsis, were selected. The CDSS was constructed by incorporating the drug, patient, dosage, pharmacodynamic, and microbiological factors. The CatBoost ML algorithm was used to build the CDSS. Real-world studies were used to evaluate the CDSS performance. Virtual trials were used to compare the CDSS-optimized doses with guideline-recommended doses. FindingsFor a specific drug, by entering the patient characteristics and pharmacodynamic (PD) target (50%/70%/100% fraction of time that the free drug concentration is above the minimal inhibitory concentration [fT>MIC]), the CDSS can determine whether the planned dosing regimen will achieve the PD target and suggest an optimal dose. The prediction accuracy of all five drugs was > 80.0% in the real-world validation. Compared with the PopPK model, the overall accuracy, precision, recall, and F1-Score improved by 10.7%, 22.1%, 64.2%, and 43.1%, respectively. Using the CDSS-optimized doses, the average probability of target concentration attainment increased by 58.2% compared to the guideline-recommended doses. InterpretationAn ML-based CDSS was successfully constructed to assist clinicians in selecting optimal β-lactam antibiotic doses. FundingThis work was supported by the National Natural Science Foundation of China; Distinguished Young and Middle-aged Scholar of Shandong University; National Key Research and Development Program of China.

Difficulties associated with the interpretation of postmortem toxicology.

While postmortem (PM) toxicology results provide valuable information towards ascertaining both the cause and manner of death in coronial cases, there are also significant difficulties associated with the interpretation of PM drug levels. Such difficulties are influenced by several pharmacokinetic and pharmacodynamic factors including PM redistribution, diffusion, site-to-site variability in drug levels, different drug properties and metabolism, bacterial activity, genetic polymorphisms, tolerance, resuscitation efforts, underlying conditions, and the toxicity profile of cases (i.e. single- or mixed-drug toxicity). A large body of research has been dedicated for better understanding and even quantifying the influence of these factors on PM drug levels. For example, several investigative matrices have been developed as potential indicators of PM redistribution, but they have limited practical value. Reference tables of clinically relevant therapeutic, toxic, and potentially fatal drug concentrations have also been compiled, but these unfortunately do not provide reliable reference values for PM toxicology. More recent research has focused on developing databases of peripheral PM drug levels for a variety of case-types to increase transferability to real-life cases and improve interpretations. Changes to drug levels after death are inevitable and unavoidable. As such, guidelines and practices will continue to evolve as we further our understanding of such phenomena.

#1838 SGLT2 computational structural studies investigating polypharmacy

Abstract Background and Aims Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients will be prescribed these compounds resulting in polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport. Method The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models and MODELLER was used to incorporate MAP-17 and empaglifozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The centroid of a 5 nanosecond GROMACS molecular dynamics (MD) equilibration was used for docking studies using PLANTS. A bespoke tool was used to identify compounds interacting with key protein residues. CHARM-GUI and bespoke software were used to prepare membrane-bound systems to run in GROMACS using GPU's in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events. Results The SGLT2-MAP17 structure in the inward-open conformation obtained showed good agreement with published structures. Existing SGLT2i (empaglifozin, dapaglifozin, canaglifozin, ertuglifozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions might provide competitive inhibition for SGLT2i compounds currently used. The compounds identified have no hitherto recognised interactions with SGLT2i; nor do they result in adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications.

Pharmcokinetic and pharmacodynamic considerations for the anticholinergic burden scale of drugs.

Older adults frequently have many systemic diseases that require treatment with multiple drugs, and thus anticholinergic adverse effect by polypharmacy is a significant concern in the management of older adults. The accuracy of the anticholinergic burden rating may be increased by considering pharmacokinetic and pharmacodynamic factors such as biophase drug concentrations, the pharmacologically active metabolites formed after drug administration, and muscarinic receptor-mediated effects. Therefore, a pharmacological evidence-based burden scale that considers pharmacokinetic and pharmacodynamic factors is expected to be a more optimal tool for precisely assessing the anticholinergic burden, specifically risk reductions in anticholinergic adverse events in the poly-medicated elderly. Geriatr Gerontol Int 2024; 24: 81-87.

Pharmacists And Herbal Medications: Identifying Potential Interactions With Conventional Drugs

Herbal medications, derived from plants, have a long history of use in various cultures for their potential therapeutic effects. They are often perceived as natural and safe alternatives to conventional pharmaceuticals. However, many patients incorporate herbal remedies into their daily routines without considering potential interactions with their prescribed medications. Commonly used herbal medications include Echinacea, Ginkgo biloba, St. John's Wort, Turmeric (curcumin), Garlic, Ginseng, and Milk thistle, each with its purported uses. While these herbs have been used for generations, their safety and effectiveness may vary, and not all herbal remedies are supported by robust scientific evidence. Pharmacists play a crucial role in ensuring patient safety and optimal therapeutic outcomes when it comes to identifying and managing drug interactions with herbal medications. Their roles include medication review and assessment, risk assessment and evaluation, patient education, communication with healthcare providers, and meticulous documentation and record-keeping. Interactions between herbal medications and conventional drugs can affect drug absorption, distribution, metabolism, and excretion. Pharmacists assess these interactions based on pharmacokinetic and pharmacodynamic factors, considering individual patient characteristics, medication importance, scientific evidence, and more. They educate patients about the risks and benefits of combining herbal and conventional treatments, empowering them to make informed choices. Pharmacists also communicate effectively with healthcare teams, provide valuable information, and report adverse events to regulatory agencies. Medication reconciliation during transitions of care, such as hospital admissions and discharges, ensures treatment continuity and patient safety. Documentation and record-keeping are crucial for maintaining accurate medication profiles, documenting assessments, and adhering to legal requirements. In summary, pharmacists play a pivotal role in recognizing, assessing, and managing potential interactions between herbal medications and conventional drugs. Their expertise ensures patient safety, effective treatment, and well-informed healthcare decisions in this complex landscape of healthcare.

From cis-Lobeline to trans-Lobeline: Study on the Pharmacodynamics and Isomerization Factors.

Lobeline is an alkaloid derived from the leaves of an Indian tobacco plant (Lobelia inflata), which has been prepared by chemical synthesis. It is classified as a partial nicotinic agonist and has a long history of therapeutic usage ranging from emetic and respiratory stimulant to tobacco smoking cessation agent. The presence of both cis and trans isomers in lobeline is well known, and many studies on the relationship between the structure and pharmacological activity of lobeline and its analogs have been reported. However, it is a remarkable fact that no studies have reported the differences in pharmacological activities between the two isomers. In this article, we found that different degrees of isomerization of lobeline injection have significant differences in respiratory excitatory effects in pentobarbital sodium anesthetized rats. Compared with cis-lobeline injections, the respiratory excitatory effect was significantly reduced by 50.2% after administration of injections which contained 36.9% trans-lobeline. The study on the influencing factors of isomerization between two isomers shown that this isomerization was a one-way isomerism and only converted from cis to trans, where temperature was the catalytic factor and pH was the key factor. This study reports a new discovery. Despite the widespread use of ventilators, first-aid medicines such as nikethamide and lobeline has retired to second line, but as a nonselective antagonist with high affinity for a4b2 and a3b2 nicotinic acetylcholine receptors (nAChRs). In recent years, lobeline has shown great promise as a therapeutic drug for mental addiction and nervous system disorders, such as depression, Alzheimer disease and Parkinson disease. Therefore, we suggest that the differences between two isomers should be concerned in subsequent research papers and applications.

Pharmacogenetic markers to predict safety of antipsychotics in adolescents experiencing acute psychotic episodes

Introduction There are relatively fewer pharmacogenetic studies of antipsychotics in adolescents than in adult patients. The development of personalized pharmacotherapy is promising.ObjectivesIdentify the most significant pharmacogenetic predictors of antipsychotic safety in adolescents experiencing acute psychotic episodesMethods The study included 101 adolescents diagnosed with acute polymorphic psychotic disorder at the time of admission (F23.0-9 according to ICD-10). All patients were taking an antipsychotic as their main treatment for 14 days. Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I), UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS) were used. All study participants underwent pharmacogenetic testing of pharmacokinetic and pharmacodynamic factors.Results CYP2D6 “intermediate” metabolism increased the risk of developing an adverse reaction by a trend of significance (OR=2.616 (95% CI 0.950-7.203); p=0.063). Carriage of HTR2A rs6313 was associated with a lower score on the UKU SERS “Other Symptoms” subscale (Beta=(-0.289); p=0.003) and an objective score on the BARS akathisia severity scale (Beta=(-0.217); p=0.029). DRD3 rs324026 carriers had a lower BARS akathisia scale score (Beta=(-0.349); p=0.004); DRD3 rs6280 carriers had a lower SAS extrapyramidal symptom severity scale score (Beta=(-0.351); p=0.003). Carriers of ANKS1B rs7968606 were associated with a higher SAS scale score (Beta=0.237; p=0.017).ConclusionsWe proposed that genotyping of CYP2D6*4, *10, DRD3 rs324026 (C allele), DRD3 rs6280 (C allele), HTR2A rs6313 (TT genotype) and ANKS1B rs7968606 (T allele) will predict the high risk of intolerance to antipsychotics in adolescents with acute psychotic episodes.DisclosureNo significant relationships.

Exploring the usefulness of plasma level determination and pharmacogenetics for patients treated with clozapine.

Aims: The aims of the present study were to assess the variance of plasma clozapine (CLZ) levels and to identify the influence of sociodemographic and pharmacogenetic factors on it and to introduce these tools in a clinical setting. Patients & methods: CLZ concentration was measured and genetic variants of CLZ pharmacokinetic and pharmacodynamic factors were assessed in 23 patients with psychotic disorders. Results: A significant association between mean concentration/dose ratio (C/D) and smoking status, age and weight were found. There was a significant difference in mean plasma CLZ levels and gender. The rs762551 AA genotype in smokers had a significantly lower C/D. Conclusion: In addition to classical factors, monitoring of plasma concentrations together with pharmacogenetics led to greater individualization of treatment.

A pharmacokinetic and pharmacodynamic analysis of drug forgiveness.

Nonadherence to medication is a major public health problem. To combat nonadherence, some clinicians have suggested using "forgiving" drugs, which maintain efficacy in spite of delayed or missed doses. What pharmacokinetic (PK) and pharmacodynamic (PD) factors make a drug forgiving? In this paper, we address this question by analyzing a linear PK/PD model for a patient with imperfect adherence. We assume that the drug effect is far from maximal and consider direct effect, effect compartment (biophase), and indirect response PD models. We prove that the average drug effect relative to the clinically desired effect is simply the fraction of prescribed doses actually taken by the patient. Hence, under these assumptions, drug forgiveness cannot be defined in terms of the average effect. We argue that forgiveness should instead be understood in terms of effect fluctuations. We prove that the rates of PK absorption, PK elimination, and PD elimination are exactly equivalent for determining effect fluctuations. We prove all the aforementioned results for any pattern of nonadherence, including late doses, missed doses, drug holidays, extra doses, etc. To obtain quantitative estimates of effect fluctuations, we consider a simple statistical pattern of nonadherence and analytically calculate the coefficient of variation of effect. We further show how effect fluctuations can be reduced by taking an extra "make up" dose following a missed dose if any one of the aforementioned PK/PD rates is sufficiently slow. We illustrate some of our results for a nonlinear indirect response model of metformin.

TREN PENGGUNAAN ANTIBIOTIKA LINI 3 DI RS X BEKASI PERIODE TRIWULAN I TAHUN 2020 DIBANDINGKAN DENGAN TRIWULAN IV TAHUN 2019

Antibiotics are the most widely used drugs in the treatment of infections caused by bacteria. Resistance of microorganisms to antibiotics, pharmacokinetic and pharmacodynamic factors, drug interactions and side effects and cost factors are needed to be considered in their use. The use of antibiotics needs to be evaluated quantitatively and qualitatively. The study was conducted to determine and evaluate the use of line 3 antibiotics quantitatively in the X Bekasi Hospital in the first quarter of 2020 compared to the fourth quarter of 2019. It was descriptive study with retrospective data collection using total sampling technique. There are 13 types of antibiotics that are included in the line 3 antibiotics used at X Bekasi Hospital. The percentage of use of line 3 antibiotics in the first quarter of 2020 compared to the fourth quarter of 2019 increased by 26.9% for the use of amikacin 250 mg injection but decreased by 100% for the use of amikacin 500 mg injection, increased by 17.8% for the use of meropenem 0.5 g injection but decreased by 16.1% for the use of meropenem 1 g injection, decreased by 100% for the use of imipenem-cilastatin injection, linezolid 600 mg injection and vancomycin 500 mg injection, decreased by 212.5%, 53.6%, 41.2% and 69.2% each for the use of doripenem 500 mg injection, decreased, ceftazidime 1 g injection, cefepime 1 g injection and piperacillin tazobactam injection, and increased 75% for the use of tigecycline 50 mg injection. The use of line 3 antibiotics in X Bekasi Hospital was very large and varied in the fourth quarter of 2019 compared to the first quarter of 2020. A very significant amount was seen in the use of imipenem-cilastatin injection, linezolid 600 mg injection and vancomycin 500 mg injection.

Phase Lag Entropy as a Surrogate Measurement of Hypnotic Depth during Sevoflurane Anesthesia.

Background and Objectives: Phase lag entropy, an electroencephalographic monitor, evaluates the variety in temporal patterns of phase relationship between frontal and prefrontal brain region. Phase lag entropy can reflect the depth of anesthesia induced by propofol, but the association between sevoflurane and phase lag entropy has not been elucidated. This study examined the effect of sevoflurane on phase lag entropy during induction of general anesthesia. We also explored the pharmacodynamic model between end-tidal anesthetic concentration and electroencephalographic monitor. Materials and Methods: A total of 20 patients were enrolled. General anesthesia was produced by escalating the sevoflurane (1 vol% up to 8 vol%). The relationship between phase lag entropy and end-tidal anesthetic concentration was analyzed. A non-linear mixed-effects model was used to get the relationship of pharmacodynamics between the end-tidal sevoflurane concentration and phase lag entropy. Mean blood pressure, heart rate, and the modified observer’s assessment of alertness/sedation scale were also recorded during sevoflurane anesthesia. Results: As level of sedation increased, phase lag entropy decreased. A significant correlation was showed between phase lag entropy and end-tidal sevoflurane concentration (r = −0.759, p < 0.001). The correlation coefficient between the modified observer’s assessment of alertness/sedation scale and phase lag entropy was 0.731 (p < 0.001). The pharmacodynamic factors assessed by the sigmoid Emax model were E0 = 84.9, Emax = 42, Ce50 = 1.81, γ = 4.78, and ke0 = 0.692. The prediction probability of phase-lag entropy for measuring the modified observer’s assessment of alertness/sedation scale and end-tidal sevoflurane concentration were 0.764 and 0.789, respectively. With the increasing concentration of sevoflurane, mean blood pressure decreased, but heart rate did not change. Conclusions: The continuing escalation in end-tidal sevoflurane concentration caused a decline in phase lag entropy. Phase lag entropy can serve as an indicator of hypnotic depth in patients receiving sevoflurane anesthesia.

Analysis of associations between pharmacodynamic genetic factors and antipsychotics’ effectiveness and safety in adolescents with acute psychotic episodes taking antipsychotics during a 28-day follow-up

Introduction. Antipsychotics are the main drugs for treatment of schizophrenia spectrum disorders. Pharmacodynamic genetic factors are being actively studied to improve the accuracy of antipsychotic selection based on pharmacogenetic testing.Purpose of this study: to establish associations of genetic polymorphisms of the DRD2, DRD3, DRD4, HTR2A, COMT, ZNF804A, and ANKS1B genes with the efficacy and safety of antipsychotics in adolescents with an acute psychotic episode during a 28-day follow-up.Materials and methods. The study included 68 adolescents with an established diagnosis of acute polymorphic psychotic disorder at the time of admission (F23.0-9 according to ICD-10). All patients received an antipsychotic as their main therapy. Patients were monitored for 28 days. The effectiveness of antipsychotics was assessed using the Children’s Global Assessment Scale (CGAS), Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I). The safety of pharmacotherapy was assessed using the UKU Side Effects Rating Scale (UKU SERS), Sympson-Angus Scale (SAS), Barnes Akathisia rating scale (BARS). From each patient we obtained a buccal scraped epithelium, extracted DNA from it by sorbent method and detected carriage of genetic polymorphisms DRD2 rs1800497 (C&gt;T), DRD3 rs6280 (C&gt;T), DRD3 rs324026 (C&gt;T), DRD4 rs1800955 (C&gt;T), HTR2A rs6313 (T&gt;C), COMT rs4680 (Val158Met, G&gt;A), ZNF804A rs1344706 (A&gt;C), ANKS1B rs7968606 (C&gt;T) by real-time PCR.Results. DRD2 rs1800497 T allele carriers had a stronger reduction in the PANSS subscore «Productive Symptomatics» on day 14 (Me=-7.0 [-9.0;-5.0] vs Me=-7.0 [-8.0;-2.0]; p=0.018) and day 28 of follow-up (Me=-11.0 [-9.0;-5.5] vs Me=-8.0 [-8.0;-2.0]; p=0.019). Also, greater improvement on the CGAS scale on day 14 of follow-up was seen in TC+CC HTR2A rs6313 carriers (Me=2.0 [1.0;3.0] vs. Me=2.0 [1.0;2.0]; p=0.029). DRD3 rs324026 homozygous carriers (TT) had a significantly lower SAS score (Me=0.5 [0.0; 1.0] vs. Me=1.0 [0.0; 5.0]; p=0.016) and UKU subscore «Neurological Disorders» on 28 days of antipsychotic therapy (Me=0.0 [0.0; 0.0] vs. Me=1.0 [0.0; 3.8]; p=0.005). DRD3 rs324026 TT carriers also had lower severity of akathisia according to the BARS scale. Carriers of the T DRD4 rs1800955 allele had a higher SAS scale score on day 28 of therapy compared with CC homozygotes (Me=1.0 [0.0;4.0] vs Me=0.0 [0.0;1.0]; p=0.036).Conclusion. The DRD2 rs1800497 was a predictor of better reduction of productive symptoms; HTR2A rs6313 demonstrated a similar association. The DRD2 rs1800497 polymorphic variant was a predictor of better reduction of productive symptomatology; HTR2A rs6313 demonstrated a similar association. DRD3 rs324026 and HTR2A rs6313 were associated with a lower frequency of neurological adverse reactions and akathisia. In contrast, carriers of the DRD4 rs1800955 were more prone to adverse reactions on pharmacotherapy.

Managing uncertainty in antifungal dosing: antibiograms, therapeutic drug monitoring and drug-drug interactions.

A number of pharmacokinetic and pharmacodynamic factors in critically ill or severely immunosuppressed patients influence the effectiveness of antifungal therapy making dosing less certain. Recent position papers from infectious diseases societies and working groups have proposed methods for dosage individualization of antibiotics in critically ill patients using a combination of population pharmacokinetic models, Monte-Carlo simulation and therapeutic drug monitoring (TDM) to guide dosing. In this review, we examine the current limitations and practical issues of adapting a pharmacometrics-guided dosing approaches to dosing of antifungals in critically ill or severely immunosuppressed populations. We review the current status of antifungal susceptibility testing and challenges in incorporating TDM into Bayesian dose prediction models. We also discuss issues facing pharmacometrics dosage adjustment of newer targeted chemotherapies that exhibit severe pharmacokinetic drug-drug interactions with triazole antifungals. Although knowledge of antifungal pharmacokinetic/pharmacodynamic is maturing, the practical application of these concepts towards point-of-care dosage individualization is still limited. User-friendly pharmacometric models are needed to improve the utility of TDM and management of a growing number of severe pharmacokinetic antifungal drug-drug interactions with targeted chemotherapies.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Drug Treatment of Non-Tuberculous Mycobacteria in Cystic Fibrosis.

Non-tuberculous mycobacteria (NTM) are an emerging group of pulmonary infectious pathogens of increasing importance to the management of patients with cystic fibrosis (CF). NTM include slow-growing mycobacteria such as Mycobacterium avium complex (MAC) and rapidly growing mycobacteria such as Mycobacterium abscessus. The incidence of NTM in the CF population is increasing and infection contributes to significant morbidity to the patient and costs to the health system. Treating M. abscessus requires the combination of multiple costly antibiotics for months, with potentially significant toxicity associated with treatment. Although international guidelines for the treatment of NTM infection in CF are available, there are a lack of robust pharmacokinetic studies in CF patients to inform dosing and drug choice. This paper aims to outline the pharmacokinetic and pharmacodynamic factors informing the optimal treatment of NTM infections in CF.

Principles of Pharmacotherapy of Seizures and Status Epilepticus.

Status epilepticus is a neurological emergency with an outcome that is highly associated with the initial pharmacotherapy management that must be administered in a timely fashion. Beyond first-line therapy of status epilepticus, treatment is not guided by robust evidence. Optimal pharmacotherapy selection for individual patients is essential in the management of seizures and status epilepticus with careful evaluation of pharmacokinetic and pharmacodynamic factors. With the addition of newer antiseizure agents to the market, understanding their role in the management of status epilepticus is critical. Etiology-guided therapy should be considered in certain patients with drug-induced seizures, alcohol withdrawal, or autoimmune encephalitis. Some patient populations warrant special consideration, such as pediatric, pregnant, elderly, and the critically ill. Seizure prophylaxis is indicated in select patients with acute neurological injury and should be limited to the acute postinjury period.

Pharmacokinetic and Pharmacodynamic Factors Contribute to Synergism between Let-7c-5p and 5-Fluorouracil in Inhibiting Hepatocellular Carcinoma Cell Viability.

Pharmacological interventions for hepatocellular carcinoma (HCC) are hindered by complex factors, and rational combination therapy may be developed to improve therapeutic outcomes. Very recently, we have identified a bioengineered microRNA let-7c-5p (or let-7c) agent as an effective inhibitor against HCC in vitro and in vivo. In this study, we sought to identify small-molecule drugs that may synergistically act with let-7c against HCC. Interestingly, we found that let-7c exhibited a strong synergism with 5-fluorouracil (5-FU) in the inhibition of HCC cell viability as manifested by average combination indices of 0.3 and 0.5 in Hep3B and Huh7 cells, respectively. By contrast, coadministration of let-7c with doxorubicin or sorafenib inhibited HCC cell viability with, rather surprisingly, no or minimal synergy. Further studies showed that protein levels of multidrug resistance–associated protein (MRP) ATP-binding cassette subfamily C member 5 (MRP5/ABCC5), a 5-FU efflux transporter, were reduced around 50% by let-7c in HCC cells. This led to a greater degree of intracellular accumulation of 5-FU in Huh7 cells as well as the second messenger cyclic adenosine monophosphate, an endogenous substrate of MRP5. Since 5-FU is an irreversible inhibitor of thymidylate synthetase (TS), we investigated the interactions of let-7c with 5-FU at pharmacodynamic level. Interestingly, our data revealed that let-7c significantly reduced TS protein levels in Huh7 cells, which was associated with the suppression of upstream transcriptional factors as well as other regulatory factors. Collectively, these results indicate that let-7c interacts with 5-FU at both pharmacokinetic and pharmacodynamic levels, and these findings shall offer insight into molecular mechanisms of synergistic drug combinations.SIGNIFICANCE STATEMENTCombination therapy is a common strategy that generally involves pharmacodynamic interactions. After identifying a strong synergism between let-7c-5p and 5-fluorouracil (5-FU) against hepatocellular carcinoma cell viability, we reveal the involvement of both pharmacokinetic and pharmacodynamic mechanisms. In particular, let-7c enhances 5-FU exposure (via suppressing ABCC5/MRP5 expression) and cotargets thymidylate synthase with 5-FU (let-7c reduces protein expression, whereas 5-FU irreversibly inactivates enzyme). These findings provide insight into developing rational combination therapies based on pharmacological mechanisms.

Infant drug exposure via breast milk.

More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.

Analgesic treatment with buprenorphine should be adapted to the mouse strain

Buprenorphine is a commonly used opioid to treat moderate to severe pain in mice. Although strain differences regarding basal pain sensitivity and the analgesic effect of other opioids have been described for mice, the data for buprenorphine is incomplete. Hence, we investigated basal pain sensitivity and the analgesic effect of buprenorphine (0.42, 4.0 mg·kg−1) in male C57BL/6J, Balb/cJ and 129S1/SvImJ mice using the incremental hot plate. Additionally, we verified single nucleotide polymorphisms in Cytochrome P450 3a (Cyp3a) genes, which encode for enzymes that are relevant for buprenorphine metabolism, and analyzed serum and brain concentrations of buprenorphine and its metabolites. Finally, in a pilot survey we determined μ-opioid receptor (MOR) protein expression in whole brain lysates.Basal pain sensitivity differed significantly between the mouse strains (Balb/cJ > C57BL/6J > 129S1/SvImJ). Additionally, buprenorphine showed a dose- and strain-dependent effect: at a higher dose it led to increased antinociception in C57BL/6J and Balb/cJ mice, whereas in 129S1/SvImJ mice this effect was diminished. Serum and brain concentrations of buprenorphine and its metabolites dose-dependently increased and differed slightly between the strains at the high dose. However, these slight strain differences did not correlate with pain behavior. Furthermore, serum buprenorphine metabolic ratio and distribution of buprenorphine and its metabolites between brain and blood showed no dose- and only some strain-dependent differences independent from nociceptive behavior. Western blot analysis revealed no strain difference in the basal MOR protein expression in brain lysates.Our results indicate that buprenorphine dosing should be determined in a pilot study for the respective mouse strain to optimize pain treatment and to avoid unwanted side effects. The present pharmacokinetic data and the coarse determination of MOR expression do not explain the strain differences in the analgesic effect of buprenorphine. However, follow-up studies focusing on more specific pharmacodynamic factors could further elucidate the reasons.