Blood Drug Concentration Research Articles

Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4years old after liver transplantation and to develop individualized tacrolimus dosing software. A total of 663 blood concentrations from 85 patients aged 4.57months to 3.97years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

In Vitro and In Vivo Drug Release from a Nano-Hydroxyapatite Reinforced Resorbable Nanofibrous Scaffold for Treating Female Pelvic Organ Prolapse.

Pelvic prolapse stands as a substantial medical concern, notably impacting a significant segment of the population, predominantly women. This condition, characterized by the descent of pelvic organs, such as the uterus, bladder, or rectum, from their normal positions, can lead to a range of distressing symptoms, including pelvic pressure, urinary incontinence, and discomfort during intercourse. Clinical challenges abound in the treatment landscape of pelvic prolapse, stemming from its multifactorial etiology and the diverse array of symptoms experienced by affected individuals. Current treatment options, while offering relief to some extent, often fall short in addressing the full spectrum of symptoms and may pose risks of complications or recurrence. Consequently, there exists a palpable need for innovative solutions that can provide more effective, durable, and patient-tailored interventions for pelvic prolapse. We manufactured an integrated polycaprolactone (PCL) mesh, reinforced with nano-hydroxyapatite (nHA), along with drug-eluting poly(lactic-co-glycolic acid) (PLGA) nanofibers for a prolapse scaffold. This aims to offer a promising avenue for enhanced treatment outcomes and improved quality of life for individuals grappling with pelvic prolapse. Solution extrusion additive manufacturing and electrospinning methods were utilized to prepare the nHA filled PCL mesh and drug-incorporated PLGA nanofibers, respectively. The pharmaceuticals employed included metronidazole, ketorolac, bleomycin, and estrone. Properties of fabricated resorbable scaffolds were assessed. The in vitro release characteristics of various pharmaceuticals from the meshes/nanofibers were evaluated. Furthermore, the in vivo drug elution pattern was also estimated on a rat model. The empirical data show that nHA reinforced PCL mesh exhibited superior mechanical strength to virgin PCL mesh. Electrospun resorbable nanofibers possessed diameters ranging from 85 to 540 nm, and released effective metronidazole, ketorolac, bleomycin, and estradiol, respectively, for 9, 30, 3, and over 30 days in vitro. Further, the mesh/nanofiber scaffolds also liberated high drug levels at the target site for more than 28 days in vivo, while the drug concentrations in blood remained low. This discovery suggests that resorbable scaffold can serve as a viable option for treating female pelvic organ prolapse.

Chitosan-modified dihydromyricetin liposomes promote the repair of liver injury in mice suffering from diabetes mellitus

Liver injury caused by type-II diabetes mellitus (DM) is a significant public-health concern worldwide. We used chitosan (CS) to modify dihydromyricetin (DHM)-loaded liposomes (DL) through charge interaction. The effect of CS-modified DL (CDL) on liver injury in mice suffering from DM was investigated in vivo and in vitro. CDL exhibited superior antioxidant capacity and stability. Pharmacokinetic analyses revealed a 3.23- and 1.92-fold increase in the drug concentration–time curve (953.60 ± 122.55 ng/mL/h) in the CDL-treated group as opposed to the DHM-treated group (295.15 ± 25.53 ng/mL/h) and DL-treated group (495.31 ± 65.21 ng/mL/h). The maximum drug concentration in blood (Tmax) of the CDL group saw a 2.26- and 1.21-fold increase compared with that in DHM and DL groups. We observed a 1.49- and 1.31-fold increase in the maximum drug concentration in blood (Cmax) in the CDL group compared with that in DHM and DL groups. Western blotting suggested that CDL could alleviate liver injury in mice suffering from DM by modulating inflammatory factors and the transforming growth factor-β1/Smad2/Smad3 signaling pathway. In conclusion, modification of liposomes using CS is a viable approach to address the limitations of conventional liposomes and insoluble drugs.

Ginger oil-loaded transdermal adhesive patch treats post-traumatic stress disorder

ObjectiveTo find a viable alternative to reduce the number of doses required for the patients with post-traumatic stress disorder (PTSD), and to improve efficacy and patient compliance. MethodsIn this study, we used ginger oil, a phytochemical with potential therapeutic properties, to prepare ginger oil patches. High-performance liquid chromatography (HPLC) was used to quantify the main active component of ginger oil, 6-gingerol. Transdermal absorption experiments were conducted to optimize the various pressure-sensitive adhesives and permeation enhancers, including their type and concentration. Subsequently, the ginger oil patches were optimized and subjected to content determination and property evaluations. A PTSD mouse model was established using the foot-shock method. The therapeutic effect of ginger oil patches on PTSD was assessed through pathological sections, behavioral tests, and the evaluation of biomarkers such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), and melatonin (MT). ResultsThe results demonstrated that ginger oil patches exerted therapeutic effects against PTSD by inhibiting inflammatory responses and modulating MT and BDNF levels. Pharmacokinetic experiments revealed that ginger oil patches maintained a stable blood drug concentration for at least one day, addressing the rapid metabolism drawback of 6-gingerol and enhancing its therapeutic efficacy. ConclusionsGinger oil can be prepared as a transdermal drug patch that meets these requirements, and the bioavailability of the prepared patch is better than that of oral administration. It can improve PTSD with good patient compliance and ease of administration. Therefore, it is a promising therapeutic formulation for the treatment of PTSD.

Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 3: Theoretical models of drug concentration in blood

In this part, drug concentration in blood after ingesting slow-release gastroretentive fibrous dosage forms and immediate-release particulate forms is modeled. The tyrosine kinase inhibitor nilotinib, which is slightly soluble in low-pH gastric fluid but practically insoluble in pH-neutral intestinal fluid is used as drug. The models suggest that upon ingestion, the fibrous dosage form expands, is retained in the stomach for prolonged time, and releases drug into the gastric fluid at a constant rate. The released drug molecules flow into the duodenum with the gastric fluid, and are absorbed by the blood. The drug is eliminated from the blood by the liver at a rate proportional to its concentration. Eventually, the elimination and absorption rates will be equal, and the drug concentration in blood plateaus out. After the gastric residence time drug absorption stops, and the drug concentration in blood drops to zero. By contrast, after administering an immediate-release particulate dosage form the drug particles are swept out of the stomach rapidly, and drug absorption stops much earlier. The drug concentration in blood rises and falls without attaining steady state. The gastroretentive fibrous dosage forms enable a constant drug concentration in blood for drugs that are insoluble in intestinal fluids.

Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 4: Experimental validation of the models of drug concentration in blood

In this final part, the models of drug concentration in blood developed in Part 3 are validated on dogs. Both slow-release gastroretentive fibrous and immediate-release particulate dosage forms containing 200 mg nilotinib were tested. After administering, the fibrous dosage form expanded linearly with time in the stomach, to about 1.5 times the initial radius by 4 h. The expanded dosage form fractured after 10 h, and then passed into the intestines. The drug concentration in blood exhibited a broad peak with a maximum of 0.51 μg/ml and a width at half-height of 10.2 h. By contrast, after administering the immediate-release capsule the drug concentration in blood exhibited a sharp peak with a maximum of 0.68 μg/ml and a width at half-height of just 3.6 h. The experimental data validate the theoretical models reasonably. The gastroretentive fibrous dosage forms designed in this study enable a steady drug concentration in blood for increasing the efficacy and mitigating side effects of drug therapies.

Therapeutic Drug Monitoring Characteristics in a City Hospital for a Year.

Therapeutic drug monitoring (TDM) involves the measurement of drug concentrations in serum, plasma, whole blood, or other biologic fluids. This study focused on evaluating the TDM requests of a city hospital over a period of one year, retrospectively. The study retrospectively analyzed TDM requests for carbamazepine, cyclosporine-A, digoxin (DIGOX), lithium (LITH), methotrexate (MTX), phenitoin, tacrolimus, and valproic acid (VALP) from June 1, 2022, to June 1, 2023. Parameters such as the age and the gender of patients, the requesting departments, the measurement results, and the turnaround time (TAT) were assessed. Drug concentrations below the reference values were classified as subtherapeutic, whereas concentrations above the reference values were considered supratherapeutic. In total, 10,913 drug concentration measurement records were analyzed. The gender distribution was 51.6% male and 48.4% female. Pediatric samples comprised 6.2% and elderly samples 8.6% of the total. Notably, DIGOX, LITH, and VALP levels showed a significant correlation with age (p = < 0.0001, p = < 0.0001, and p = 0.0002, respectively). TAT was maintained at 360 minutes (6 hours) for all tests. The study found significant correlations between age and DIGOX, LITH, and VALP levels. TDM plays a critical role in the elderly population, necessitating careful management of these drugs.

Fluorodeschloroketamine found as a street drug in drug seizures and drug driving cases in Hong Kong

BackgroundWith the decline of the use of ketamine, one of the common drugs of abuse in Hong Kong, detection of ketamine-related analogues in local laboratories has been encountered. Aim: A brief account of the occurrence of fluorodeschloroketamine (FDCK) in forensic cases is reported through a retrospective study of all drug seizures and driving under the influence of drugs (DUID) cases since its first appearance. Methods: Identification of FDCK in drug seizures was achieved through gas chromatography – mass spectrometry (GC-MS) and/or liquid chromatography – diode array detection (LC-DAD) methods while its quantification was performed using gas chromatography – flame ionization detection (GC-FID). For the analysis of blood samples in DUID cases, identification and quantification were performed using LC-MS/MS by monitoring the respective transitions of FDCK and fluorodeschloronorketamine (FDCNK) using ketamine-d4 and norketamine-d4 respectively as internal standards. Results: Since its first submission in November 2018, a total of 74 drug seizure cases (151 items) and 6 drug driving cases were encountered till December 2019. Drug seizures found with FDCK were physically similar to those of ketamine seizures. The majority of items were detected with FDCK only (103 items, ∼67%) or as a mixture of FDCK with ketamine (42 items, ∼28%). The drug purity detected with either FDCK only or FDCK mixed with ketamine was high which was similar to those purity found in ketamine seizures. The blood drug concentrations of FDCK of the 6 drug driving cases were in the range of <0.002–1.1 μg/mL and other psychoactive drug(s)/metabolite(s) were also identified. Except for one case where the analysis of the metabolite, fluorodeschloronorketamine (FDCNK), was not conducted due to insufficient sample, the FDCK (FDCNK) concentrations in blood found in the 6 cases were <0.002 (0.005), 0.002 (0.002), 0.002 (0.003), 0.02 (0.035), 0.87 (0.44) and 1.1 (not determined) μg/mL. Conclusions: With the drug seizures found with FDCK resembled in physical appearance with ketamine seizures, users might likely misuse it as ketamine. Though complicated by other drugs found, it is speculated that the two cases with higher concentration of FDCK found in blood (1.1 and 0.87 μg/mL) might have contributed to the impairment observed.

LC-MS/MS and EMIT measure the whole blood concentration of cyclosporine A: The two methods yield concordant results within the dynamic range of the latter, but the former shows broader application scenarios

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500–2000 ng/mL and that of the EMIT was 40–500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200–500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of −18.0 % (±1.96 SD, −73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Effect of Therapeutic Drug Monitoring on Adherence and Blood Pressure: A Multicenter Randomized Clinical Trial.

Drug concentration in blood or urine is an acknowledged method to detect nonadherence. Observational studies suggest that informing patients about low or absent serum drug levels improves blood pressure (BP). We performed a multicenter randomized clinical trial to test the hypothesis that therapeutic drug monitoring (TDM) could improve drug adherence and BP in patients with uncontrolled hypertension (HT). Patients were ≥18 years on stable treatment with at least 2 antihypertensive agents. We planned to randomize 80 nonadherent patients with a systolic daytime ambulatory BP ≥135 mm Hg to TDM intervention or not. The control group and the study personnel who measured BP remained uninformed about serum drug measurements throughout. All patients and physicians were blinded for BPs. Lifestyle advice and detailed information on the disease process and the importance of BP treatment were given to both groups. From 2017 to 2022, we randomized 46 diagnosed nonadherent from a total of 606 patients with uncontrolled HT. The TDM group had a 6.7 (±14.5) mm Hg reduction from 147.9 (±10.3) to 141.1 (±14.1) mm Hg, and the control group experienced a 7.3 (±13.2) mm Hg reduction from 147.1 (±9.2) to 139.1 (±17.4) mm Hg, P = 0.9 between groups. Adherence improved in both groups, 73% in the TDM group and 59% in the control group became adherent at 3 months, P = 0.51. In our prospective multicenter clinical trial of uncontrolled and nonadherent hypertensive patients, we found no additional effect of TDM on BP and drug adherence compared with standard care. Trial Number NCT03209154, www.clinicaltrials.gov.

Evaluation of a miniature mass spectrometer based point-of-care-test method for direct analysis of amlodipine and benazepril in whole blood

A miniature mass spectrometer (mMS) based point-of-care testing (POCT) method was evaluated for on-site detecting the hypertension drugs, amlodipine and benazepril. The instrument parameters, including voltage, ISO1, ISO2, and CID, were optimized, under which the target compounds could be well detected in MS2. When these two drugs were injected simultaneously, the mutual ionization inhibition and mutual reduction between amlodipine and benazepril were evaluated. This phenomenon was severe on the precursor ions but had a small impact on the product ions, thus making this POCT method suitable for analysis using product ions. Finally, the method was validated and applied. The blood samples from patients were tested one hour after oral administration of the drugs (20 mg), and the benazepril was quantitatively analyzed using a standard curve, with detected concentrations ranging from 190.6 to 210 μg L−1 and a relative standard deviation (RSD) of 8.6 %. In summary, amlodipine has low sensitivity and can only be detected at higher concentrations, while benazepril has high sensitivity, good linearity, and even meets semi-quantitative requirements. The research results of this study are of great clinical significance for monitoring blood drug concentrations during hypertension medication, predicting drug efficacy, and customizing individualized medication plans.

Xintongtai Granule: Investigating the serum pharmacology and mechanisms of action against atherosclerosis

PurposeA serum medicinal chemistry analysis was performed to investigate the pharmacological basis of Xintongtai granule and to predict the potential mechanism of anti-atherosclerotic action based on the blood components. MethodsUPLC-Q-TOF-MS/MS was used to analyze the in vitro chemical composition and in vivo blood components of Xintongtai granule, and to detect the blood drug concentration. The PPI network was constructed by collecting blood components and disease targets through the network pharmacology method, and the key targets were subjected to GO and KEGG functional enrichment analyses, so as to construct the topology network of drug-component-target-disease, and to validate the network by molecular docking. ResultsThe UPLC-Q-TOF-MS/MS analysis identified 69 chemical components in Xintongtai granule, including 19 prototype circulating components and 9 metabolites in the bloodstream. Network pharmacology analysis revealed 115 intersecting targets for the circulating components, from which 10 core targets were selected. GO and KEGG analyses unveiled associated signaling pathways and biological processes. The construction of a topology network and preliminary molecular docking provided insights into its mechanism of action. ConclusionThe mechanism underlying the anti- atherosclerosis effect of Xintongtai granule may be associated with the intervention of active components such as Cryptotanshinone, Kaempferitrin, and Puerarin in pathways targeting CXCL8, STAT3, TNF, and other related targets.

Clinical Insights into Antipsychotics and Rifampicin Interaction: A Case Report

IntroductionAntipsychotics are the primary class of drugs used to manage schizophrenia. These medications help control and reduce the severity of these symptoms, allowing individuals with schizophrenia to better function. On the other hand, rifampicin, used as treatment for tuberculosis, is a powerful inducer of several drug-metabolizing enzymes which have the potential to decrease the plasma levels of antipsychotics. Therefore, the presence of multiple pharmacokinetic interactions can alter how antipsychotics are metabolized, leading to a notable clinical impact when these medications are administered concurrently.ObjectivesThe objective is to share valuable clinical experiences and insights to aid healthcare providers in making informed decisions when faced with the challenge of co-administering antipsychotics with rifampicin, ultimately ensuring the safety and efficacy of treatment for their patients.MethodsIt will be discussed a case of a 41-year-old woman with the diagnosis of schizophrenia under treatment with paliperidone palmitate and clozapine who had a sudden relapse after starting treatment for latent tuberculosis with rifampicin as a framework for a literature review based off Pubmed.Results The antituberculosis drug rifampicin induces drug-metabolizing enzymes in the liver, having the greatest effects on the expression of cytochrome P450 (CYP3A4) and therefore can lead to a decrease in the plasma levels of antipsychotic medications that also rely on these pathways for clearance. In this particular case, although specific data on clozapine and paliperidone concentrations were not reported, fluctuations in symptomatology following rifampicin introduction were probably explained by an inducing effect of this drug on their metabolism. So, when initiating rifampicin treatment and when discontinuing it, clinicians should carefully assess the dosages of any concomitant medications that may potentially interact with rifampicin. To ensure effective therapy during rifampicin treatment, it is crucial to monitor both the patient’s clinical response and their blood drug concentrations, making dosage adjustments as necessary.ConclusionsThis case report offers valuable guidance to clinicians on safely and effectively managing drug interactions between antipsychotic medications and rifampicin, ensuring the well-being of their patients during treatment. The co-administration of these medications lacks robust clinical evidence, and notably, there is insufficient data regarding its impact on plasma antipsychotic levels, a crucial factor in determining clinical effectiveness.Disclosure of InterestNone Declared

Transdermal diffusion research on functional substances of Jingu Zhitong Gel

This study systematically explored the transdermal diffusion law of functional substances of Jingu Zhitong Gel(JGZTG). The transdermal diffusion research methods of JGZTG were investigated by single factor trial with the automated transdermal(dry-heat) sampling system. High performance liquid chromatography(HPLC) content determination method was established to determine the contents of ferulic acid, senkyunolide I, cinnamic acid, hydroxy-ε-xanthoxylin, hydroxy-α-xanthoxylin, and hydroxy-β-xanthoxylin in the transdermal diffusion solution of JGZTG. The transdermal diffusion law of the components within 16 h was investigated. The results showed that the optimal transdermal diffusion method of JGZTG was as follows: Rat skin was used as the transdermal barrier; normal saline was used as the receiving medium; the dosage of JGZTG was 0.3 g, and the receiving solution was extracted by ethyl acetate. The results of transdermal diffusion showed that the release of ferulic acid, cinnamic acid, and senkyunolide I increased significantly at 0-8 h and slowed down at 8-16 h. The drug release was a synergic process of diffusion and dissolution, in which ferulic acid and cinnamic acid followed Higuchi and Ritger-Peppas equations, and liguolactone I followed Higuchi equation. The transdermal diffusion curves of hydroxy-ε-zanthoxylin, hydroxy-α-zanthoxylin, and hydroxy-β-zanthoxylin showed continuous release within 16 h, and the drug release was skeleton dissolution. The diffusion law followed zero-order equation, first-order equation, and Ritger-Peppas equation. In clonclusion, it is a controlled release of ferulic acid, ligustrone I, cinnamic acid, hydroxy-ε-pyrroxylin, hydroxy-α-pyrroxylin, and hydroxy-β-pyrroxylin in JGZTG, which can maintain stable blood drug concentration with 16 h, and the cumulative transmittance of each component with 12 h can reach 80% of cumulative transmittance with 24 h, which is in line with the clinical drug use law of bis in die.

Improvement of liraglutide release from PLGA microspheres by a porous microsphere-gel composite system

In the current work, we aimed to prepare a liraglutide-loaded porous microsphere-gel composite system. By employing polyethylene glycol (PEG) as a porogenic agent and poly (lactic-co-glycolic acid) copolymer (PLGA) as a carrier, the liraglutide microspheres were prepared and dispersed in a temperature-sensitive gel made of poloxamer 407 (F-127) and poloxamer 188 (F-68), which served as the gel matrix, to construct the composite system. The porous microsphere-gel composite system demonstrated prolonged and steady drug release, with a reduction to 4.7% in the initial release within 1 d, according to data from in vitro release tests. The drug release from the porous microspheres decreased from 53% to 29% during the rapid release phase as the PEG concentration increased and the release rate slowed down. In vivo experiments in rats revealed that the composite system prolonged the release period by about 10 d. The pharmacokinetic parameter AUC0-1 was decreased by 24.78 ng/ml*h, the initial burst release was decreased, and the blood drug concentration fluctuation was lessened. The construction of a porous microsphere-gel composite matrix offers a novel approach to the systems with a sustained, long-lasting release that utilizes rational design.

Comparative analysis of post-mortem drug concentrations in cerebrospinal fluid and blood.

This study aimed to compare the concentration of various xenobiotics in both cerebrospinal fluid (CSF) and blood. We examined 175 autopsy cases covering a wide range of ages, causes of death, and drug ingestion histories, with cerebrospinal fluid and blood samples available for toxicological testing. Analytes studied included opioids, benzodiazepines, antidepressants, antipsychotics, and illicit substances such as cannabinoids, stimulants and new psychoactive substances, including synthetic cathinones and synthetic cannabinoids. We found that concentrations in CSF were generally lower than in blood. A significant correlation was observed between drug concentrations in CSF and blood for many analytes (p < 0.05). However, the strength and direction of the correlation varied considerably depending on the physicochemical properties of the drugs, suggesting that a 'one size fits all' model may not be applicable. The results indicate that cerebrospinal fluid (CSF) can be used to detect a variety of xenobiotics, particularly amphetamines, synthetic cathinones and synthetic cannabinoids, in cases where conventional biological materials are not available. Additionally, using the results obtained in the future can lead to a better understanding of pharmacokinetic processes and the effect of post-mortem redistribution. Further research is needed to refine our understanding of these relationships.

Conversion From Immediate-Release to Prolonged-Release Tacrolimus in Kidney Transplant Patients With Tremor: A Case Series Study

Background/AimTremor is common with tacrolimus treatment and is linked with peak blood drug concentrations. We investigated the effect of switching from immediate-release tacrolimus (IR-TAC) to MeltDose prolonged-release tacrolimus (LCPT) on tremor in kidney transplant recipients experiencing tremor at therapeutic levels of IR-TAC. MethodsThe Activities of Daily Living Subscale (ADL, range 0-48, lower = better) of the Essential Tremor Rating Scale was used to assess the effect of therapy change on speech, occupational impairment and social activities over a 12-month follow-up period. ResultsThe study included 18 patients (mean age = 45.6 y, range 26-73; median (IQR) time from transplant = 1.1 y (0.6-1.5), with baseline IR-TAC trough concentrations (C0) ranging from 4.2 to 9.4 ng/mL (mean C0 = 6.7 ± 1.3 ng/mL). After the switch to LCPT, the mean ADL score improved from baseline 11.2 to 8.4 after 7 to 14 days (an 18% improvement, P < .001). This improvement was sustained after 3 months (ADL score = 5.0, 46% improvement vs baseline), 6 months (ADL score = 4.4, 48% improvement vs baseline), and 12 months (ADL score = 3.6, 63% improvement vs baseline); all P < .001. Despite a 40% reduction in LCPT daily doses (mean −1.9 mg/day compared to IR-TAC), the achieved C0 was constant during the course of the 12-month observation (P = .755). The renal function remained stable after conversion (eGFR 12 months vs baseline = +1.1 mL/min/1.73 m2, 95% CI: −5.6 to +7.9). ConclusionConversion to LCPT may alleviate symptom burden and improve daily activities in kidney transplant recipients experiencing tremor within therapeutic IR-TAC concentrations.

Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 μL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C_(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 μm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T_(max) of 15 min and 30 min, the C_(max) of(2 866.43±135.39) and(1 462.14±197.38) μg·L~(-1), the AUC_(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) μg·min·L~(-1), the MRT_(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL_Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of &quot;automatic blood collection-microdialysis/PK-PD&quot; in the research on neuropathic pain.

Effect of continuous renal replacement therapy on the clinical efficacy and pharmacokinetics of polymyxin B in the treatment of severe pulmonary infection

ObjectiveThis study aimed to evaluate the pharmacokinetics of polymyxin B in patients with ventilator-associated pneumonia caused by multi-drug resistant bacteria, and to analyze the effect of continuous renal replacement therapy (CRRT) on pharmacokinetics of polymyxin B. MethodsThirty-five patients with ventilator-associated pneumonia caused by multi-drug resistant bacteria admitted to our hospital from June 2021 to January 2022 were selected as the subjects. The patients were divided into the standard group (n = 20) and the non-standard group (n = 15) based on the factors affecting the compliance of polymyxin B plasma concentration. The patients received with polymyxin B and the plasma concentration was monitored. According to the monitoring results, they were divided into the standard group and the non-standard group, to analyze the influencing factors of polymyxin B on the blood concentration. Besides, the patients were then divided into the control group (n = 28) and the observation group (n = 7) according to whether the patients received CRRT treatment. Patients in the control group treated with polymyxin B alone, while patients in the observation group received with polymyxin B and CRRT. The general data of patients in the two groups were compared. The levels of plasma concentration of polymyxin B measured before the next administration (Cmin), peak plasma concentration of polymyxin B measured immediately after end of infusion (Cmax) and intermediate plasma concentration measured 6 h after administration (midpoint of the dosing interval) (C1/2t) were detected and compared between the two groups. Correlation between pharmacokinetics and efficacy was analyzed by Spearman correlation. The incidence of complications and the 28-day mortality rate of the two groups were recorded. ResultsThe age, body mass index (BMI) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores in the non-standard group were higher than these in the standard group (p < 0.05). BMI and APACHE II scores were independent risk factors affecting the pharmacokinetics of polymyxin B in patients with severe pulmonary infection (p < 0.05). There were no significant differences in age, BMI, APACHEII score, alanine aminotransferase level, aspartate aminotransferase level, albumin level, gender and diabetes ratio between the control group and the observation group (p > 0.05). The levels of Cmin, Cmax, and C1/2t in the observation group were lower than these in the control group (p < 0.001). The response rate was 50.00% in the control group and 36.36% in the observation group (p > 0.05). The levels of Cmin, Cmax, and C1/2t in the observation group were no significant correlation with the clinical efficacy (p > 0.05), while these in the control group were positive correlation with the clinical efficacy (r = 0.485, p < 0.05). There was no significant difference in the incidence of skin pigmentation, nephrotoxicity and 28-day mortality between the two groups (p > 0.05). ConclusionIn patients with ventilator-associated pneumonia not receiving multidrug-resistant bacteria, the rate of achieving blood drug concentration with the usual recommended dose of polymyxin B was satisfactory. However, the proportion of patients with a 6-h plasma concentration exceeding the maximum plasma concentration was high. BMI and APACHE II scores were important factors affecting the pharmacokinetics of polymyxin B. In patients undergoing CRRT, the plasma concentration of polymyxin B was significantly reduced, suggesting that in patients with severe disease, plasma concentration monitoring played an important role in drug efficacy and patient safety. In patients treated with CRRT, the dose of polymyxin B may need to be increased.