Plasma Drug Concentrations Research Articles

Population pharmacokinetics, enzyme occupancy, and 24S-hydroxycholesterol modeling of soticlestat, a novel cholesterol 24-hydroxylase inhibitor, in healthy adults.

Soticlestat is a first-in-class, selective inhibitor of cholesterol 24-hydroxylase (CH24H), which catabolizes cholesterol to 24S-hydroxycholesterol (24HC) in the brain, in phase III development for Dravet syndrome and Lennox-Gastaut syndrome treatment. This study aimed to develop a model of soticlestat pharmacokinetics (PKs) and pharmacodynamics (PDs) using 24HC plasma concentrations and CH24H enzyme occupancy (EO) time profiles. Subsequently, model-based simulations were conducted to identify dosing strategies for phase II trials in children and adults with developmental and epileptic encephalopathies (DEEs). Four phase I trials of healthy adults involving oral administration of soticlestat 15-1350 mg were used to develop the mixed-effect population PK/EO/PD model. The population PK analysis utilized 1727 observations (104 individuals), PK/EO analysis utilized 20 observations (11 individuals), and PK/PD analysis utilized 2270 observations (99 individuals). Optimal dosing strategies were identified from model-based PK, EO, and PD simulations. The PK/EO/PD model described the observed data well and comprised a two-compartment model with dose as a covariate on peripheral volume, linear elimination, and intercompartmental clearance. Transit and effect-site compartments were included to accommodate different dosage forms and the delay between plasma drug concentrations and EO. Model-based simulations indicated that soticlestat 100-300 mg twice daily may be an optimal adult dosing regimen with weight-adjusted pediatric dosing strategies identified for evaluation in phase II trials. The population PK/EO/PD model provided understanding of the soticlestat PK/PD relationship with partial delineation of sources of variability, and identified dosing strategies for phase II trials of children and adults with DEEs.

In vitro and in vivo anti-inflammatory, antibacterial and pharmacokinetic properties of baicalein

Baicalein is a bioactive flavone originally isolated from the roots of Scutellaria baicalensis, Scutellariala teriflora and Oroxylum indicum. The in vitro and in vivo anti-inflammatory and antibacterial properties of baicalein and pharmacokinetics after its single intramuscular administration were studied in Wistar rats. The in vitro anti-inflammatory activity of baicalein (10, 50 and 100 µM) was tested for its ability to inhibit the COX-2 enzyme by measuring PGE2 levels and determination of nitric oxide (NO) production in lipopolysaccharide (LPS) treated RAW 264.7 macrophage cells, in which baicalein was found to have significant inhibition of NO and PGE2 production in RAW 264.7 macrophage cells as compared with the LPS control group. The in vivo anti-inflammatory activity of baicalein (200 mg/kg) was assessed using the carrageenan-induced rat paw oedema model, following intramuscular injection. A significant percentage of inhibition of oedema volume was observed when compared with the carrageenan control group. In vitro and in vivo antibacterial activities of baicalein were determined by the micro broth dilution technique and neutropenic rat thigh infection model, wherein baicalein did not show any antibacterial property. Concentrations of baicalein were determined in rat plasma by high performance liquid chromatography (HPLC) after a single intramuscular administration at a dose of 200 mg/kg body weight, in which the mean peak plasma drug concentration (Cmax) of 0.77 ± 0.02 μg/mL was achieved at 0.08 h. The mean elimination half-life (t½β), the apparent volume of distribution (Vd(area)), total body clearance (Cl(B)) and mean residence time (MRT) were observed as 0.63 ± 0.06 h, 601.03 ± 28.18 L/kg, 677.39 ± 35.36 L/h/kg and 0.76 ± 0.06 h, respectively. Conclusively, in the present study, baicalein did not show in vitro or in vivo antibacterial property, but proved to have good anti-inflammatory activity. The available anti-inflammatory drugs have proved to have side effects in veterinary and human therapeutics. In this situation, baicalein may become an effective alternative to non-steroidal anti-inflammatory drugs and should also be studied in target animal species. Further research should be carried out to improve the solubility and bioavailability of baicalein through injectable routes.

Cardiac output and the pharmacology of general anesthetics: a narrative review

The relationship between cardiac output and anesthetic drugs is important to anesthesiologists, since cardiac output determines the speed with which a drug infused into the bloodstream reaches its target and the intensity of the drug’s effect. But rather than focus on how anesthetic drugs affect cardiac output, this narrative review focuses on how changes in cardiac output affect the pharmacokinetics and pharmacodynamics of general anesthetics during the three phases of anesthesia.
 At induction, an increase in cardiac output shortens both the onset time of propofol for hypnosis and the neuromuscular blocking effect of rapid-acting neuromuscular blockers, favoring the conditions for rapid sequence intubation.
 During maintenance, changes in cardiac output are followed by opposite changes in the drug plasma concentration of anesthetic drugs. Thus, an increase in cardiac output followed by a decrease in the plasma concentration of the anesthetic could expose the patient to a real risk of intraoperative awakening, which can be avoided by increasing the dose of hypnotic drugs.
 At emergence, an increase in cardiac output secondary to an increase in pCO2 allows for a more rapid recovery from anesthesia. The pCO2 can be increased by adding CO2 to the respiratory circuit, lowering the ventilatory rate, or placing the patient on partial rebreathing. Finally, the reversal action of sugammadex for rocuronium-induced neuromuscular block can be shortened by increasing the cardiac output.

Development and clinical application of a liquid chromatography-tandem mass spectrometry-based assay to quantify eight tyrosine kinase inhibitors in human plasma

IntroductionTyrosine kinase inhibitors (TKIs) are widely used in tumor treatment. The detection of these medicines by liquid chromatography-tandem mass spectrometry (LC-MS/MS) can avoid the interference of structurally similar compounds. ObjectivesThis study aimed to develop and validate a new LC-MS/MS assay for the quantification of eight tyrosine kinase inhibitors in human plasma and to preliminarily evaluate the clinical utility of the therapeutic drug monitoring method. MethodsPlasma samples were prepared by simple protein precipitation and separated using an ultra-high-performance reversed phase column. Detection was achieved using a triple quadrupole mass spectrometer in the positive ionization mode. The assay was validated against standard guidelines. We reviewed and analyzed the results of 268 plasma samples obtained from patients administered imatinib and other TKIs collected from January 2020 to November 2021 at Zhongshan Hospital. The analytes were separated and quantified within 3.5 min. ResultsThe newly developed method demonstrated linearity for the detected drug concentration in the range of 20 to 2000 ng/ml for gefitinib (r2 = 0.991) and crizotinib (r2 = 0.992), 50 to 5000 ng/ml for nilotinib (r2 = 0.991) and imatinib (r2 = 0.995), 1500–150,000 ng/ml for vemurafenib (r2 = 0.998), 1000–100,000 ng/ml for pazopanib (r2 = 0.993), 0.5–100 ng/ml for axitinib (r2 = 0.992) and 5–500 ng/ml for sunitinib (r2 = 0.991) and N-desethyl sunitinib (r2 = 0.998). The lower limit of quantification (LLOQ) was 20 ng/ml for gefitinib and crizotinib, 50 ng/ml for nilotinib and imatinib, 1500 ng/ml for vemurafenib, 1000 ng/ml for pazopanib, 0.5, and 5 ng/ml for sunitinib and N-desethyl sunitinib, respectively. Specificity, precision, accuracy, and stability were tested, and met the requirements of the guidelines. At the same dose, there was no significant difference in plasma drug concentration between the original imatinib medicine and the generic medicine after patent expiration. ConclusionWe developed a sensitive and reliable method for the quantification of eight TKIs.

Pharmacokinetics of Marbofloxacin Following Oral Administration in Lactic Acid Pretreated Broiler Chickens

Background: It is hypothesized that feeding lactic acid as a feed additive has the potential to alter the pharmacokinetics of many antimicrobial drugs being used for the treatment of infectious disease in general and marbofloxacin in particular; leading to either increased or decreased efficiency. Hence, the present study was planned to explore the effects of lactic acid pre-treatment on the pharmacokinetics of marbofloxacin after oral administration in broiler chickens. Methods: The pharmacokinetics of marbofloxacin was investigated following single dose oral administration (5 mg/kg) in lactic acid pre-treated (8 gm/l each, oral, 10 days) broiler chickens. The plasma concentration of marbofloxacin was determined by ultra-high-performance liquid chromatography to workout pharmacokinetic profile of marbofloxacin using non compartment model. Result: The AUC (area under curve) of marbofloxacin declined from 14.70 ìg·h/mL to 6.16 ìg·h/mL after pre-treatment of lactic acid. Similarly, the average values of maximum plasma concentration (Cmax) of drug decreased from 2.11 ìg/mL to 0.98 ìg/mL and mean body clearance (ClB) increased from 0.47 L/h/kg to 1.03 L/h/kg. The average elimination half-lives (t½â) of marbofloxacin before and after pre-treatment with lactic acid were 4.89 h and 2.81 h, respectively. Furthermore, the investigation revealed alteration of pharmacokinetic parameters evident in lactic acid pre-treated broiler chickens (as compared to non pre-treated birds) requiring adjustment of dosage regimens.

Silk fibroin carriers with sustained release capacity for treating neurological diseases.

Neurological diseases such as traumatic brain injury, cerebral ischemia, Parkinson's, and Alzheimer's disease usually occur in the central and peripheral nervous system and result in nervous dysfunction, such as cognitive impairment and motor dysfunction. Long-term clinical intervention is necessary for neurological diseases where neural stem cell transplantation has made substantial progress. However, many risks remain for cell therapy, such as puncture bleeding, postoperative infection, low transplantation success rate, and tumor formation. Sustained drug delivery, which aims to maintain the desired steady-state drug concentrations in plasma or local injection sites, is considered as a feasible option to help overcome side effects and improve the therapeutic efficiency of drugs on neurological diseases. Natural polymers such as silk fibroin have excellent biocompatibility, which can be prepared for various end-use material formats, such as microsphere, gel, coating/film, scaffold/conduit, microneedle, and enables the dynamic release of loaded drugs to achieve a desired therapeutic response. Sustained-release drug delivery systems are based on the mechanism of diffusion and degradation by altering the structures of silk fibroin and drugs, factors, and cells, which can induce nerve recovery and restore the function of the nervous system in a slow and persistent manner. Based on these desirable properties of silk fibroin as a carrier with sustained-release capacity, this paper discusses the role of various forms of silk fibroin-based drug delivery materials in treating neurological diseases in recent years.

Pharmacokinetic-pharmacodynamic (PK/PD) modeling to study the hepatoprotective effect of Perilla Folium on the acute hepatic injury rats

Ethnopharmacological relevancePerilla Folium (PF), is a traditional medicinal material with the homology of medicine and food in China and has been widely used due to its rich nutritional content and medicinal value. The hepatoprotective effects of PF extract include their protection against acute hepatic injury, tert-butylhydroperoxide (t-BHP) induced oxidative damage, and Lipopolysaccharide (LPS) and D-galactosamine (D-GalN) induced hepatic injury have been well studied. However, there are few reports on the pharmacokinetics studies of PF extract in acute hepatic injury model rats, and the anti-hepatic injury activity of PF is still unclear. Aim of the studyThe differences in the plasma pharmacokinetic of 21 active compounds between the normal and model groups were compared， and established pharmacokinetics/pharmacodynamics (PK/PD) modeling was to analyze the hepatoprotective effects of PF. Materials and methodsThe acute hepatic injury model was induced with an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN), and the plasma pharmacokinetics of 21 active compounds of PF were analyzed in the normal and model groups using ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS). The correlation between plasma components and hepatoprotective effects indicators (the alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactic dehydrogenase (LDH)) in the model group was also investigated and established a Pharmacokinetic/pharmacodynamic (PK/PD) correlation analysis of the hepatoprotective effects of PF. ResultsThe results revealed that organic acid compounds possessed the characteristics of faster absorption, shorter peak time and slower metabolism, while the flavonoid compounds had slower absorption and longer peak time, and the pharmacokinetics of various components were significantly affected after modeling. The results of PK/PD modeling analysis demonstrated that the plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long. ConclusionsThe plasma drug concentration of each component existed a good correlation with the three AST, ALT, and LDH, and the lag time of the efficacy of each component is relatively long in vivo.

Advancement in oral pharmacokinetics of an antibiotic Cefixime using amphiphilic 4-armed macrocyclic surfactant based niosomes

The four -armed long carbon chains supramolecular amphiphilic macrocycles are able to self-assemble into nanosized architectures called niosomes that have a membrane bilayer structure. In this study, amphiphilic macrocycle (MCC10) was synthesized by the cyclization of alkylated 4-hydroxybenzaldehyde with resorcinol, in acidic medium acting as a catalyst as well as a solvent, and Cefixime (Cef) was used as model entrapment drug. The drug loaded MCC10 noisomes were characterized by various spectroscopic techniques including; Maldi Toff MS, 1HNMR and FTIR. MCC10 niosomes were subjected to biocompatibility and blood haemolysis using NIH/3T3 cell line and fresh human red blood cells (RBCs), respectively. Acute toxicity study was conducted in mice. The drug loading efficiency was studied by HPLC while shape and size of MCC10 macrocycle was investigated using atomic force microscope (AFM), scanning electron microscopy (SEM) and dynamic light scattering (DLS), respectively. In-vivo oral pharmacokinetic was evaluated in rabbits. The shape of drug loaded macrocycle (Cef-MCC-10) was spherical with average size of 200.1 ± 2.24 nm, and zeta potential −18.0 ± 0.8 mV, having polydispersity index (PDI) of 0.07 and showing greater drug entrapment efficiency (%EE) of 72.86 ± 3.31%. The average size of unloaded vesicles of MCC10 was 157.7 ± 2.02 nm, the zeta potential value for unloaded formulation of MCC10 was −11.5 ± 0.71 mV, and whereas, the polydispersity index was found to be 0.24. MCC10 was screened for cell cytotoxicity study using NIH/3T3 and Hela cells at the highest concentration of 1000 μg/mL where they better cell viability of 71.00 ± 2.10% and 68.00 ± 2.15%, respectively. MCC10 niosomes showed in-vivo drug plasma concentration (Cmax) of10.29 ± 4.81 μg/mL for Cef that was higher than commercially available suspension and capsules. Therefore, MCC10 is presented as effective and safe nano-carrier for Cef to improve the oral pharmacokinetics in rabbits.

Effect of a decoction of Lophira alata (Banks ex P. Gaertn) on the pharmacokinetics of risperidone: Study of a drug-herb interaction

Drug interactions may cause a drug to be more or less effective (synergism or antagonism), or cause unexpected effects on the body. Risperidone is a second-generation atypical antipsychotic medication while Lophira alata is a plant used traditionally to treat psychotic disorders. A large number of patients with psychosis have been reported to simultaneously use both orthodox and traditional medicines in Africa. This research was carried out to determine the effect of concomitant administration of risperidone and Lophira alata in healthy human volunteers. The first phase of the research was carried out to establish the baseline pharmacokinetic profile of risperidone 2 mg in 18 male subjects. The second phase was carried out after a 2-week washout period, where the subjects were randomly divided into three equal groups and group A received risperidone 2 mg and decoction of the herb (9.4mg/kg) concurrently, group B received risperidone 2 mg and decoction of the herb (9.4mg/kg) was administered after 1 hour and group C received a decoction of the herb (9.4mg/kg) and risperidone 2 mg was administered after 1 hour. Blood samples were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after drug administration, and plasma analyses were carried out using a developed RP-HPLC method to determine the plasma concentrations. Subsequently, Kinetica 5.0 software was used to extrapolate pharmacokinetic parameters from the plasma concentrations. Results show that there was a significant (p < 0.05) increase in the rate of absorption (ka), peak plasma concentration (Cmax) and measure of drug exposed to the body (AUC0-∞) but significant (p < 0.05) decrease in the time to achieve peak plasma concentration (tmax), half-life of absorption (t1/2a) and extent of drug distribution (Vd) when risperidone and Lophira alata were administered concurrently. Drug-herb interaction was observed to be more significant (p < 0.05), when Lophira alata was administered concurrently with risperidone than when administered one hour before or after Lophira alata. Decoction of Lophira alata interacts with risperidone tablets when administered together, which may be attributed to alteration in the mechanism of risperidone absorption by Lophira alata.

Prolonged Anesthesia Induction to Delivery Time Did Not Influence Plasma Remifentanil Concentration in Neonates.

Remifentanil, in combination with etomidate and sevoflurane, is commonly used in clinics for general anesthesia induction in cesarean section (CS). This study aimed to evaluate the correlation between the induction to delivery (I-D) time and neonatal plasma drug concentration and anesthesia, as well as its effects on neonates. Fifty-two parturients in whom general anesthesia was induced for CS were divided into group A (I-D<8 min) and group B (I-D≥8 min). Maternal arterial (MA), umbilical venous (UV), and umbilical arterial (UA) blood samples were collected at delivery to analyze the remifentanil and etomidate concentrations using liquid chromatography-tandem mass spectrometry. There were no statistically significant differences between the two groups in terms of plasma concentrations of remifentanil in the MA, UA, and UV blood (P > 0.05). The plasma concentration of etomidate in MA and UV was higher in group A than that in group B (P<0.05), whereas the UA/UV ratio of etomidate was higher in group B than that in group A (P<0.05). The Spearman rank correlation test showed no correlation between the I-D time and plasma remifentanil concentration in the MA, UA, and UV plasma (P>0.05). The concentrations of etomidate in the MA and UV were negatively correlated with the I-D time (P < 0.05). Prolonged I-D time did not significantly influence the maternal or neonatal plasma concentration of remifentanil. It is safe to administer remifentanil target-controlled infusion in combination with etomidate and sevoflurane for general anesthesia induction during CS.

A strategy for low-cost portable monitoring of plasma drug concentrations using a sustainable boron-doped-diamond chip

On-site monitoring of plasma drug concentrations is required for effective therapies. Recently developed handy biosensors are not yet popular owing to insufficient evaluation of accuracy on clinical samples and the necessity of complicated costly fabrication processes. Here, we approached these bottlenecks via a strategy involving engineeringly unmodified boron-doped diamond (BDD), a sustainable electrochemical material. A sensing system based on a ∼1 cm2 BDD chip, when analysing rat plasma spiked with a molecular-targeting anticancer drug, pazopanib, detected clinically relevant concentrations. The response was stable in 60 sequential measurements on the same chip. In a clinical study, data obtained with a BDD chip were consistent with liquid chromatography–mass spectrometry results. Finally, the portable system with a palm-sized sensor containing the chip analysed ∼40 μL of whole blood from dosed rats within ∼10 min. This approach with the ‘reusable’ sensor may improve point-of-monitoring systems and personalised medicine while reducing medical costs.

The Influence of Cytochrome P450 Polymorphisms on Pharmacokinetic Profiles and Treatment Outcomes Among Malaria Patients in Sub-Saharan Africa: A Systematic Review.

Sub-Saharan Africa (SSA) population is genetically diverse and heterogenous thus variability in drug response among individuals is predicted to be high. Cytochrome P450 (CYP450) polymorphisms is a major source of variability in drug response. This systematic review presents the influence of CYP450 single nucleotide polymorphisms (SNPs), particularly CYP3A4*1B, CYP2B6*6 and CYP3A5*3 on antimalarial drug plasma concentrations, efficacy and safety in SSA populations. Searching for relevant studies was done through Google Scholar, Cochrane Central Register of controlled trials (CENTRAL), PubMed, Medline, LILACS, and EMBASE online data bases. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were used. Two independent reviewers extracted data from the studies. Thirteen studies reporting the influence of CYP450 SNPs on plasma concentrations, efficacy and safety were included in the final data synthesis. CYP3A4*1B, CYP3A5*5, CYP2B6*6 and CYP2C8*2 did not affect antimalarial drug plasma concentration significantly. There was no difference in treatment outcomes between malaria patients with variant alleles and those with wild type alleles. This review reports lack of influence of CYP3A4*1B, CYP3A5*3, CYP2C8*3 and CYP2B6*6 SNPs on PK profiles, efficacy and safety in SSA among P. falciparum malaria patients.

Exploration of melt granulation technique for the development of entecavir monohydrate tablets using 32 factorial designs

This research work aims to fabricate fast-release tablets of entecavir monohydrate using a novel melt granulation technique and optimize the proportion of xylitol and mannitol using a 32 factorial design. entecavir monohydrate, a medication used for treating hepatitis B virus (HBV) infection, was used as a model drug. The fast-release tablets were designed to avoid fluctuations in plasma drug concentration and increase the bioavailability of entecavir monohydrate. The FTIR spectra of pure entecavir monohydrate were compared against polymers which had no interaction. The pre-compression and post-compression parameters were found to be within the desired range. The results of the drug release studies indicate that the formulations were able to release the drug within the desired range of 60-80% within 10 minutes. The study concludes that the melt granulation technique can be used to develop fast-release tablets of entecavir monohydrate with good compressibility, flow characteristics, and mechanical strength.

Bioequivalence study of generic nirmatrelvir in healthy volunteers

Nirmatrelvir is an antiviral drug that, in combination with ritonavir, is an effective agent for the etiotropic therapy of patients with mild to moderate COVID-19.The aim of the study was to evaluate bioequivalence of the generic drug nirmatrelvir Аrpaxel in combination with ritonavir and the original drug Paxlovid, which is a combination of nirmatrelvir/ritonavir, in a single dose administration to healthy volunteers.Materials and methods. This research was an open-label, randomized, two-period crossover bioequivalence study. It included 2 periods, in each of which the volunteers received either a test drug (nirmatrelvir at the dose of 300 mg) in combination with ritonavir (100 mg), or a reference drug (a combination of nirmatrelvir 300 mg and ritonavir 100 mg), given as a single dose. A wash-out period between each of the administrations was 7 days. The blood sampling to determine the concentration of nirmatrelvir was carried out in the range from 0 to 36 h in each of the study periods. A nirmatrelvir concentration was determined by a validated HPLC-MS/MS method with a lower quantitation limit of 10 ng/mL. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC(0–16) and Cmax of the test drug and reference drugs with the established equivalence limits of 80.00–125.00%.Results. In the study were included 68 healthy volunteers, 67 participants of which were included in the bioequivalence population. The pharmacokinetic parameters of the drugs were comparable to each other. The 90% confidence interval for the ratio of the geometric mean of the maximum drug concentration in the blood plasma and the area under the pharmacokinetic curve «concentration-time» from zero to the last blood draw within 36 hours of nirmatrelvir was 87.26–100.83 and 93.27–103.74%, which meets the criteria for assessing bioequivalence. The test drugs were well tolerated by the volunteers. The incidence of adverse events was similar for the test and reference drugs. No serious adverse events were recorded during the entire study.Conclusion. As a result of this study, bioequivalence of the test and reference drugs has been established.

Pluronic F-68 Montmorillonite As A Drug Delivery Vehicle For Extended Release Of Venlafaxine Hydrochloride.

Short half-life and low bioavailability of Venlafaxine hydrochloride (VF), an antidepressant drug, necessitates the frequent administration of VF tablets in a day in order to maintain adequate drug concentration in blood plasma. This generates the need for the development of formulations which could prolong the release of VF and reduce the multiple dosages. The present work explores the combination of Montmorillonite (Mt) with Pluronic F-68 (PF-68) (OrganoMT) for oral delivery of VF. The effect of various parameters including pH of aqueous drug solution, contact time and initial drug concentration on drug loading capacity of OrganoMT has been studied. The synthesized OrganoMT-VF complexes were characterized by various suitable techniques. XRD studies indicated that the VF molecules were intercalated within the OrganoMT layers. In vitro release behavior of VF from OrganoMT-VF complexes shows an extended-release pattern for a period of 30 h and reaches upto 70% and 60% compared to pure VF having complete release time of 5.5 h and 3.5 h in simulated gastric and intestinal fluid respectively. Various kinetic models were employed to elucidate the drug release mechanism where the best fitting was obtained with Korsmeyer Peppas model. The results suggest the possibility of designing an oral extended controlled release formulation for VF to minimize its administration frequency thereby increasing the effectiveness of drug. This improves patient compliance by reducing the dose from 4 times in 24 h to once in 24 h.

Extracorporeal circulation in the elderly: anesthesia in patients undergoing myocardial revascularization in the intensive care unit (ICU)

To describe cardiopulmonary bypass in the elderly under anesthesia of patients undergoing myocardial revascularization in the Intensive Care Unit. Cardiopulmonary bypass (CPB) can alter plasma concentrations of drugs used during anesthesia for cardiac surgery and cause effects on the central nervous system, leading patients to a greater degree of sedation, which alters the time of patient awakening. Method: This is a descriptive-qualitative-exploratory study, of a comprehensive nature, of the systematic type. Results: The three groups were compared in terms of weight, height, age and body mass index (BMI). Regarding intubation time and wake-up time, it was observed that the CPB group had higher values ​​for these variables, with a significant difference. Conclusion: The short duration of action of propofol of approximately 6 to 9 minutes can be explained by the high clearance and rapid distribution of the drug. Propofol concentration at the site of action also increases rapidly due to the rapid equilibrium between plasma and brain concentrations (&lt; 4 minutes).

A Review on Modified Release Dosage Form

Among the various routes of drug delivery oral route is most preferred route. But conventional dosage form offers few limitations which could be resolved by modifying the existing dosage form. Sustained and controlled drug delivery system helps in maintaining of constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action. Modified release drug products allow at least a two-fold reduction in dosing when compared to a drug that is presented in a conventional immediate release form. Modified release drug products are designed to release active pharmaceutical ingredient over a longer duration of time; At least, longer than an Immediate release (I.R) formulation. Many Pharmaceutical companies also utilize the proprietary advantages of Modified release formulations to extend the patent life cycle of commercial products thereby bringing in new business.

A Metabolomics-Based Study on the Discriminative Classification Models and Toxicological Mechanism of Estazolam Fatal Intoxication.

Fatal intoxication with sedative-hypnotic drugs is increasing yearly. However, the plasma drug concentration data for fatal intoxication involving these substances are not systematic and even overlap with the intoxication group. Therefore, developing a more precise and trustworthy approach to determining the cause of death is necessary. This study analyzed mice plasma and brainstem samples using the liquid chromatography-high resolution tandem mass spectrometry (LC-HR MS/MS)-based metabolomics method to create discriminative classification models for estazolam fatal intoxication (EFI). The most perturbed metabolic pathway between the EFI and EIND (estazolam intoxication non-death) was examined, Both EIND and EFI groups were administered 500 mg of estazolam per 100 g of body weight. Mice that did not die beyond 8 hours were treated with cervical dislocation and were classified into the EIND groups; the lysine degradation pathway was verified by qPCR (Quantitative Polymerase Chain Reaction), metabolite quantitative and TEM (transmission electron microscopy) analysis. Non-targeted metabolomics analysis with EFI were the experimental group and four hypoxia-related non-drug-related deaths (NDRDs) were the control group. Mass spectrometry data were analyzed with Compound Discoverer (CD) 3.1 software and multivariate statistical analyses were performed using the online software MetaboAnalyst 5.0. After a series of analyses, the results showed the discriminative classification model in plasma was composed of three endogenous metabolites: phenylacetylglycine, creatine and indole-3-lactic acid, and in the brainstem was composed of palmitic acid, creatine, and indole-3-lactic acid. The specificity validation results showed that both classification models distinguished between the other four sedatives-hypnotics, with an area under ROC curve (AUC) of 0.991, and the classification models had an extremely high specificity. When comparing different doses of estazolam, the AUC value of each group was larger than 0.80, and the sensitivity was also high. Moreover, the stability results showed that the AUC value was equal to or very close to 1 in plasma samples stored at 4 °C for 0, 1, 5, 10 and 15 days; the predictive power of the classification model was stable within 15 days. The results of lysine degradation pathway validation revealed that the EFI group had the highest lysine and saccharopine concentrations (mean (ng/mg) = 1.089 and 1.2526, respectively) when compared to the EIND and control group, while the relative expression of SDH (saccharopine dehydrogenase) showed significantly lower in the EFI group (mean = 1.206). Both of these results were statistically significant. Furthermore, TEM analysis showed that the EFI group had the more severely damaged mitochondria. This work gives fresh insights into the toxicological processes of estazolam and a new method for identifying EFI-related causes of mortality.

HIV seroconversion among men who have sex with men who use event-driven or daily oral pre-exposure prophylaxis (CohMSM-PrEP): A multi-country demonstration study from West Africa.

Data on HIV seroconversion among men who have sex with men (MSM) using pre-exposure prophylaxis (PrEP) in West Africa are needed. This study aimed to document HIV seroconversion and associated determinants, PrEP adherence, plasma drug concentrations, and HIV drug resistance in MSM using event-driven or daily PrEP in Burkina Faso, Côte d'Ivoire, Mali, and Togo. A prospective cohort study was conducted in 2017-2021 among HIV-seronegative MSM aged 18 or over who were at high risk of HIV infection. Participants could choose between event-driven and daily PrEP, switch regimens, and discontinue or restart PrEP. The determinants of HIV incidence were investigated using a multivariate mixed-effects Poisson regression analysis. A total of 647 participants were followed for a total time of 1229.3 person-years. Of 5371 visits, event-driven PrEP was chosen in 3873 (72.1%), and daily PrEP in 1400 (26.1%). HIV incidence was 2.4 per 100 person-years (95% CI 1.5-3.6) for event-driven PrEP, and 0.6 per 100 person-years (95% CI 0.1-2.3) for daily PrEP (adjusted incidence rate ratio 4.40, 95% CI 1.00-19.36, p=0.050). Adequate adherence was lower with event-driven than daily PrEP (44.3% vs 74.9%, p<0.001). Plasma drug concentrations were undetectable in 92 (97.9%) of the 94 measures taken for 23 participants who seroconverted. Only 1 participant had resistance to PrEP drugs. HIV seroconversions mainly occurred in participants who chose event-driven PrEP. The study's data highlighted major difficulties with adherence to this regimen. Improving adherence to event-driven PrEP constitutes a major research and public health priority in this context.

In vivo solid phase microextraction for therapeutic monitoring and pharmacometabolomic fingerprinting of lung during in vivo lung perfusion of FOLFOX

In vivo lung perfusion (IVLP) is a novel isolated lung technique developed to enable the local, in situ administration of high-dose chemotherapy to treat metastatic lung cancer. Combination therapy using folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX) (FOLFOX) is routinely employed to treat several types of solid tumours in various tissues. However, F is characterized by large interpatient variability with respect to plasma concentration, which necessitates close monitoring during treatments using of this compound. Since plasma drug concentrations often do not reflect tissue drug concentrations, it is essential to utilize sample-preparation methods specifically suited to monitoring drug levels in target organs. In this work, in vivo solid-phase microextraction (in vivo SPME) is proposed as an effective tool for quantitative therapeutic drug monitoring of FOLFOX in porcine lungs during pre-clinical IVLP and intravenous (IV) trials. The concomitant extraction of other endogenous and exogenous small molecules from the lung and their detection via liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) enabled an assessment of FOLFOX's impact on the metabolomic profile of the lung and revealed the metabolic pathways associated with the route of administration (IVLP vs. IV) and the therapy itself. This study also shows that the immediate instrumental analysis of metabolomic samples is ideal, as long-term storage at −80 °C results in changes in the metabolite content in the sample extracts.