Background:Preeclampsia is a hypertensive pregnancy disorder marked by systemic inflammation and endothelial dysfunction. Sulfasalazine, an anti-inflammatory agent, may have therapeutic potential in preeclampsia. This study investigated its pharmacokinetics, placental transfer, and safety profile of sulfasalazine and its metabolite, sulfapyridine in women with preterm preeclampsia. Methods:A prospective, open-label pharmacokinetic trial was conducted at two hospitals in Melbourne, Australia, (February 2018-December 2020). Participants between 24+0- and 36+0- weeks' gestation with a singleton, non-anomalous pregnancies and a diagnosis of preeclampsia were included received 3 g/day of oral sulfasalazine. Serial maternal blood samples were collected post-dose. Maternal and umbilical cord blood and placental tissue were collected at birth. Primary outcomes were maternal-fetal safety and pharmacokinetics. Maternal plasma levels of soluble fml-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured. All participants receiving at least one dose were included in analyses. The trial was prospectively registered with ANZCTR (12617000226303). Findings:Twelve participants were enrolled, seven had pharmacokinetic sampling. No serious adverse events occurred relating to sulfasalazine use. Sulfasalazine and its metabolite sulfapyridine were detected in maternal plasma, placenta and in the fetal circulation. Maternal-to-fetal transfer of both compounds was confirmed, with some participants showing higher concentrations in cord blood than maternal blood, suggesting potential active or saturable transport mechanisms. Antiangiogenic biomarkers, including sFlt-1, increased post-treatment in most participants. Interpretation:Sulfasalazine was well tolerated in women with preterm preeclampsia and showed maternal and fetal exposure. Placental transfer was evident. These findings support the feasibility of sulfasalazine use in this population and warrant further investigation in a larger clinical trial to evaluate efficacy. Funding:Norman Beischer Medical Research Foundation, University of Melbourne, and NHMRC. Funders had no role in study conduct or manuscript preparation.

BACKGROUND:Multidrug-resistant tuberculosis (MDR-TB) is an urgent public health challenge in Namibia, with profound socioeconomic consequences. The high burden of both tuberculosis and HIV complicates treatment and underscores the need for optimised drug therapies. Precision medicine, which leverages patient-specific genetic and molecular information, offers promise for improving MDR-TB outcomes. However, its effective application relies on population-specific data, particularly understanding how individuals metabolise tuberculosis drugs and how genetic diversity drives variability in treatment response. Currently, no pharmacokinetic (PK) or pharmacogenetic (PG) data on TB treatment exist for Namibian populations. This gap is particularly concerning, given the country's genetic diversity, environmental factors and comorbidities that may uniquely influence drug metabolism. This study aims to generate PK and PG data to inform dose optimisation and support personalised treatment strategies for MDR-TB in Namibia. The findings will contribute to improved patient care and inform health system strengthening based on locally relevant evidence. METHODS:This cross-sectional study will consist of 100 Namibian participants with matched human DNA and PK data of MDR-TB cases receiving isoniazid, clofazimine, bedaquiline and the fluoroquinolones (levofloxacin or moxifloxacin). PK sampling will be divided as follows: 30 individuals will undergo intensive PK sampling, while the remaining (n=70) will undergo sparse PK sampling. DNA will be extracted at Stellenbosch University (SU), and samples will be genotyped using the H3Africa microarray. Sequences will be aligned to the human reference genome, hg38 (GRCh38p13), using the freely available Burrows-Wheeler Aligner. A subset of the samples (n=20-30) will undergo whole genome sequencing (WGS) to verify imputation results and identify novel genetic variants potentially affecting PK in this population. DATA ANALYSIS:Quality control and variant call format file generation will be performed using the Genome Analysis Toolkit best practices (V.3.5). Intensive and sparse PK data will be pooled for the development of a population PK (popPK) model using a non-linear mixed-effects modelling approach. The popPK model will characterise the relationship between TB drug dose and exposure, including quantifying covariates, including genetic variation, explaining PK variability, providing a foundation for dose optimisation and personalised treatment strategies. ETHICS AND DISSEMINATION:Ethics approval was obtained from the University of Namibia Human Research Ethics Committee for Health (Ref. SOM18/2024), the Ministry of Health and Social Services (Ref. 22/4/2/3), the SU Health Research Ethics Committee (Ref. N21/11/136) and the University of Cape Town Human Research Ethics Committee (Ref. 500/2022).

BACKGROUND:People with HIV (PWH) experience excess cardiovascular disease (CVD) risk with persistent inflammation considered a key driver, despite antiretroviral therapy (ART). Low-level viraemia (LLV) may contribute to inflammation and vascular injury, but data in sub-Saharan Africa are limited. We assessed correlates of endothelial function among Black African PWH with a history of viraemia despite ART use. METHODS:We conducted a cross-sectional sub-study within the South African UTRA trial (NCT05333679). Endothelial function was measured with EndoPAT using the natural log-transformed reactive hyperaemia index (LnRHI); endothelial dysfunction was defined as LnRHI≤0.51. The primary exposure was 12-month cumulative HIV viral load (VL) area-under-the-curve (AUC). Body-mass index (BMI), waist-to-hip ratio (WHR), and body roundness index (BRI) were modelled using adjusted natural cubic splines with robust standard errors. We evaluated associations of various covariates, including these body composition metrics, with LnRHI via multivariable regression. RESULTS:Of 120 participants (median age 46 years, 69% women), 26% met criteria for endothelial dysfunction despite low 10-year CVD risk. Median LnRHI was 0.69 (IQR 0.50-0.94). Mean cumulative VL AUC was 1.55 log10 copy-years/mL (IQR 1.30-2.20), consistent with LLV. Cumulative VL was not associated with endothelial function after adjustment. In contrast, LnRHI varied significantly and non-linearly across BMI, WHR, and BRI, with an overall downward trend with increasing adiposity. CONCLUSIONS:In this cross-sectional analysis of Black African PWH with LLV, no association between cumulative VL and endothelial dysfunction was observed. However, higher adiposity was consistently associated with declining endothelial function. Our data adds to the growing evidence on the importance of addressing body composition as a multifactorial risk determinant and important correlate of early vascular risk in PWH.

OBJECTIVES:To determine the PK of the pro-drug colistimethate sodium (CMS) and colistin in adult patients admitted to a South African critical care unit and to compare the PK with historical data. MATERIALS AND METHODS:We conducted a prospective, observational, PK study in critically ill adult patients receiving intravenous colistin as part of standard of care. CMS was administered as a loading dose of either 9 million units (MU) or 12 MU followed by maintenance doses dependent on creatinine clearance (CrCl) at either 12- or 8-hourly. PK samples were collected at 1, 2, 4, 8, 12, 24 and 48 hours post-loading dose. CMS and colistin concentrations were analysed using liquid chromatography-tandem mass spectrometry. The PK of CMS and colistin were described using non-compartmental analysis in Phoenix WinNonlin. RESULTS:We enrolled 24 participants, 50% (12/24) were admitted with burns. Mean age was 42 years (SD ± 16.3) and mean CrCl was 140 mL/min (SD ± 58.7). The PK parameters following a loading dose of 9 MU were comparable to published data. Colistin AUC showed a negative correlation with white cell count (r = -0.63) and eGFR (r = -0.44). Probability of target attainment was acceptable at Acinetobacter baumannii minimum inhibitory concentrations <1 mg/L. CONCLUSION:Our results are comparable to previously published literature. Notably, increasing eGFR and WCC decreased colistin AUC. Future work will adopt a population pharmacokinetic modelling approach to quantify and account for sources of variability, with the aim of informing individualized dosing strategies for this South African population.

Glyphosate, a widely used herbicide approved in over 100 countries for its broad-spectrum efficacy and low cost, has raised increasing environmental and health concerns. Monitoring inadvertent exposure requires quantification of glyphosate and its metabolites, aminomethylphosphonic acid (AMPA) and methylphosphonic acid (MPA). The Western Cape Province of South Africa, characterized by a Mediterranean climate that supports intensive agriculture, lacks biomonitoring data on these compounds. This study reports the first validated LC-MS/MS method in Southern Africa for the simultaneous quantification of glyphosate, AMPA, and MPA in human serum without derivatization, and its application to clinical samples from farming-intensive areas of the Western Cape. Calibration standards ranged from 15.0 to 760 ng/mL for glyphosate, 25.0-1600 ng/mL for AMPA, and 0.75-48 ng/mL for MPA, using Oasis MAX cartridges for extraction. Analysis was performed on a Sciex QTRAP 6500+ LC-MS/MS system with a Phenomenex Luna C8 column and gradient elution. Method validation followed SANTE/2020/12830, REV.2 guidelines, assessing linearity, limit of quantification, selectivity, matrix effects, recovery, precision, and stability. Among 258 serum samples opportunistically collected from clinics located in regions with intensive pesticide use, glyphosate and/or its metabolites were detected in 11.6% of samples, with three exhibiting quantifiable concentrations. This robust, non-derivatized LC-MS/MS method enables accurate biomonitoring of glyphosate exposure and provides the first evidence of human exposure in agricultural communities of the Western Cape.

Tuberculous meningitis (TBM) treatment outcomes are poor, partly due to suboptimal drug penetration into the cerebrospinal fluid (CSF). Little is known about the CSF pharmacokinetics of many TB drugs, both established and new. This study investigated the CSF penetration of cycloserine (administered as terizidone) and clofazimine, two core second-line drugs for drug-resistant tuberculosis (TB). We recruited participants with pulmonary drug-resistant TB, but without TBM, receiving terizidone and/or clofazimine for at least 2 weeks and collected serial plasma samples and a single CSF sample. Drug concentrations were quantified with validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were determined using noncompartmental analysis, and population pharmacokinetic modeling was used to estimate the partition coefficient and equilibration half-life. Data were available from 27 participants, with a median age of 36 (range 20-60) and a weight of 52 kg (30-73 kg), who contributed 216 plasma and 27 CSF samples. The plasma pharmacokinetics of both drugs was in line with previous reports. Terizidone, measured as cycloserine, achieved CSF exposure of 69% relative to plasma, with plasma and CSF concentrations equilibrating with a half-life of 4.7 hours. Clofazimine CSF penetration was 0.13% of plasma exposure, with an equilibration half-life of 55.4 hours. Cycloserine and clofazimine concentrations in CSF approximated their estimated unbound (active) concentration in plasma, thus suggesting good penetration of the unbound drug into the CSF, supporting their potential use in TBM regimens. This study demonstrates a feasible and reproducible method for effective assessment of CSF drug penetration for CNS infections.

Stroke among people with HIV (PWH) has been linked to initiating or reinitiating antiretroviral therapy (ART) within six months.1,2,3 We examined this association in a large prospective cohort. We conducted a descriptive interim analysis of data from the ongoing AVALON study investigating stroke in PWH (NIH-1R21TW012384-01A1). Over 12 months (September 2024–August 2025), we included all PWH presenting with neuroimaging-confirmed acute/subacute stroke (imaging within three weeks of symptom onset) to Western Cape public sector hospitals with brain imaging facilities (n = 10). We identified 605 PWH with stroke. Median age was 44 years (interquartile range [IQR] 36–54), with 51% female at birth (Table 1). Ischaemic stroke comprised 85% of cases, mostly involving the middle cerebral artery territory (63%). Previous stroke ( 4 weeks before current) was evident in 17%. At presentation, 76% were on ART for a median 8.2 years (IQR 3.8–11.9), most commonly tenofovir/lamivudine/dolutegravir (73%). ART was initiated/reinitiated within six months prior to stroke in 24.4%, with a median of 68 days (IQR 26–119) from initiation/reinitiation to stroke. ART adherence derived from pharmacy refills was 57% in the preceding six months. The most recent median viral load was 50 copies/mL (IQR 20–6777), measured a median of 85 days (IQR 4–420) before stroke. We report the largest South African cohort of PWH with stroke to date. Participants were young, on currently recommended ART, and 28% had no comorbidities. A quarter initiated/reinitiated ART within six months of stroke, supporting previous reports suggesting a potential immune reconstitution-like syndrome.

Human Immunodeficiency Virus and malaria are significant public health challenges in sub-Saharan Africa, contributing substantially to morbidity and mortality in the region. The trajectory of HIV and malaria mono- and coinfections may be different with presentations of drug-drug and disease-disease interactions. Current medications of artemether-lumefantrine and dolutegravir (DTG) -based anti-retroviral therapy which are the preferred drugs are metabolised by CYP2B6, CYP3A4/5 and UGTs which are polymorphic and may contribute to drug disposition and clinical outcomes. This study investigated the pharmacogenetic effects of co-administration of arthemeter-lumfantrine and DTG in HIV-malaria mono and coinfection. Malaria and HIV mono- and coinfected participants were recruited from health facilities in the Central region of Ghana. Blood samples were taken at pre-defined time points during malaria and HIV mono- and coinfection. Plasma drug concentrations of artemether-lumefantrine and dolutegravir and their metabolites of dihydroartemisinin and desbutyl-lumefantrine were determined by liquid chromatography–mass spectrometry (LC–MS/ MS). Genotyping for CYP2B6, UGT1A, CYP3A4 and CYP3A5 was undertaken using PCR-RFLP, TaqMan assays and Iplex GOLD SNP genotyping protocol. Two hundred and sixty-one participants were involved in this study, with a male to female ratio of 1:2. Median parasitaemia for malaria monoinfection and HIV-malaria coinfection was 947.34 parasites/µL of whole blood and 5287.36 parasites/µL of whole blood respectively on day 1. By days 3 and 7, the parasitaemia had decreased to 0 for both malaria monoinfection and HIV-malaria coinfections. Plasma median Cday 7 for lumefantrine was 741.5 (496.0, 1276.0) ng/mL for malaria monoinfection and 426.0 (254.5, 803) ng/mL for malaria and HIV coinfection (MHC) showing a decreased plasma concentration during coadministration with DTG. There was a decrease in the plasma concentration of DTG in MHC cases compared to HIV monoinfection. This trend is observed in CYP3A5 rs776746, CYP3A rs10264272, CYP3A4 rs2740574, UGT1A1 rs4148323 and CYP2B6 rs28399499 genetic variations. There is an observed decrease in plasma drug concentrations during the co-administration of artemether-lumefantrine and dolutegravir. Possible long-term effects from non-adherence may include sub-optimal levels that could result in clinical differences and outcomes.

Thiafentanil is a popular opioid agonist used for wildlife chemical immobilisation. Its effects are quickly and completely reversed by the antagonist naltrexone. Successful wildlife immobilisations using thiafentanil have been documented in a variety of wildlife species globally. The aim of this study was to describe the single-dose intramuscular (IM) and intravenous (IV) pharmacokinetics of thiafentanil in goats at a dose of 90 μg/kg using a single cross-over study. The IM dose was administered in the left Vastus lateralis. Plasma samples were collected up to 120 min after thiafentanil administration from two female and eight male adult goats. Samples were analysed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters from one and two-compartment models were estimated via a Bayesian approach. The two-compartment model was preferred overall. The estimated bioavailability was 0.677 (90% Crl: 0.542-0.888), absorption rate constant (ka) was 0.058 1/min (90% Crl: 0.045-0.115) and clearance was 29.0 mL/min/kg (90% Crl: 23.7-36.3) from this model. This study provides key pharmacokinetic data on thiafentanil, supporting a two-compartment model and offering insights into its absorption, bioavailability, and clearance when used for wildlife immobilisation.

BACKGROUND: Sertraline (SER) is a selective serotonin reuptake inhibitor (SSRI) prescribed for depression, including during pregnancy. Existing literature suggests a potential association between gestational SER use and cardiac and neurodevelopmental anomalies in exposed offspring. This study evaluated the relative impacts of SER and its metabolite desmethylsertraline (DES) on the proteome during early development. METHODS: Zebrafish embryos and larvae were exposed to individual treatments of translated umbilical cord-blood equivalent concentrations of SER or DES during early developmental stages. Quantified activity tracking and protein expression levels of serotonin transporter (SERT) were used to confirm a significant SSRI effect in exposed larvae. A whole-larvae proteomic analysis was conducted using a label-free quantitative liquid chromatography-mass spectrometry approach. Protein identification was performed using zebrafish and human protein databases. RESULTS: Apparent therapeutic SSRI effect of exposure doses of SER and DES was confirmed in zebrafish larvae, by reduced activity levels, as well as decreased SERT. DES, but not SER, resulted in several differentially regulated proteins, identified in both the zebrafish and human databases. The results from the two databases correlated and aligned with an increased risk for cardiovascular and neurodevelopmental dysregulation. CONCLUSION: Proteomic data suggest that DES, rather than SER, at physiologically relevant doses, may be responsible for adverse clinical outcomes reported after gestational SSRI use. Current data positions larval zebrafish as a possible tool for assessment of long-term risk after gestational SER use, as well as a drug development tool in this context. CLINICAL TRIAL NUMBER: N/A.

Thiafentanil is a µ-opioid agonist used for the chemical immobilisation of a variety of ungulate species and is antagonised by the administration of naltrexone. The potential for these ungulates to be hunted for consumption by humans or predators raises concerns of drug residues in animal tissues. No analytical method to quantify tissue residue concentrations of thiafentanil has been previously reported. This research developed an LC-MS/MS method to quantify thiafentanil in bovine muscle, and both thiafentanil and naltrexone in bovine liver and kidney matrices. The analytical method was applied to quantify tissue residues in samples collected from goats 1, 2, 3, and 6 days post thiafentanil administration. The assay was validated over the calibration range 6.25-200 ng/mg for thiafentanil in muscle, and 3.13-400 ng/mg for thiafentanil and 57.8-7400 ng/mg for naltrexone in liver and kidney. No residues above the lowest limit of quantification were detected in the injection site, longissimus dorsi muscle, liver or kidney samples collected from the goats. The reported analytical method and residue depletion data provide a foundation for future thiafentanil and naltrexone residue depletion studies in wildlife species.

BACKGROUND:Scalable strategies to detect and address inadequate adherence to antiretroviral therapy (ART) are a high priority towards meeting UNAIDS 95-95-95 targets. A urine tenofovir rapid assay (UTRA) at the point-of-care improves adherence among pre-exposure prophylaxis recipients and virologic suppression (VS) in a pre-post study of people with HIV (PWH). Here, we conducted the first randomized trial of UTRA-enhanced adherence support vs standard of care among PWH. METHODS:Participants receiving dolutegravir (DTG)- or protease inhibitor (PI)-based ART were randomized to UTRA-enhanced adherence support (n = 100) vs standard of care (n = 100). The primary outcome was VS, HIV-1 RNA <50 copies/mL, at 12-months and secondary outcome was VS at 6 months. To explore ART adherence over the preceding 6-8 weeks, tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) was quantified. C-reactive protein (CRP) was measured as an inflammatory marker. RESULTS:At the 12-month visit, 59/80 (74%) in the intervention and 48/75 (64%) in the control arm achieved VS (the same proportion as at 6 months; P = .2); TFV-DP concentrations (median, IQR) in DBS were significantly higher in the intervention arm: 884 (491-1296) vs 598 (239-964) fmol/3-mm DBS punch in the control arm (P < .01). Higher TFV-DP DBS concentrations correlated with a slight decrease in CRP (Spearman's rho = -0.19; P = .02). CONCLUSIONS:UTRA-enhanced adherence support did not result in a significantly higher VS rate but was associated with increased TFV-DP in DBS-in turn, associated with lower CRP levels-suggesting that UTRA-enhanced adherence support improves long-term drug exposure and could also reduce HIV-associated inflammation. CLINICAL TRIALS REGISTRATION:clinicaltrials.gov (https://clinicaltrials.gov/study/NCT05333679).

Introduction:Depression in pregnancy is common and the use of antidepressants in pregnancy, especially sertraline, is on the rise. Although sertraline is known to cross the placenta, the level of transfer to the foetus is unclear. Thus, we investigated maternal and umbilical cord blood sertraline levels following use in pregnancy. Methods:We prospectively recruited women taking sertraline during pregnancy, who were undergoing a caesarean section birth (n = 18). Maternal and umbilical cord blood samples were collected at the time of caesarean and sertraline and desmethyl sertraline concentrations measured via liquid chromatography with tandem mass spectrometry. Results:The ratio of umbilical cord to maternal plasma concentrations was calculated to determine placental transfer. Sertraline and desmethyl sertraline concentrations were consistently lower in umbilical cord blood than maternal plasma, with ratios of 0.35 for sertraline and 0.43 for desmethyl sertraline, suggesting incomplete placental transfer. Higher maternal doses and shorter intervals since the last dose correlated with higher foetal exposure. There were three preterm births (16.7%), and one baby with a major congenital abnormality (William's syndrome) among our cohort. Adverse neonatal outcomes were uncommon, with all term infants having Apgar scores > 5 at 1 and 5 min and 4 experiencing respiratory distress. Conclusion:Our findings suggest maternal use of sertraline in pregnancy results in moderate placental transfer and, thus, foetal exposure. Umbilical cord blood levels were influenced by maternal dose and timing of administration. These results may assist in shared decision-making for clinicians and patients when considering the initiation or continuation of psychotropic treatment in pregnancy.

BACKGROUND:Obesity among women with human immunodeficiency virus (WWH) is nearly 2-fold higher than in men. Obesity is closely associated with dysglycemia, and frequently necessitates the coadministration of dolutegravir and metformin. A pharmacokinetic study in 15 nonobese healthy volunteers determined that dolutegravir increased metformin plasma exposure by 79%, prompting regulatory and guideline recommendations to limit metformin to 1000 mg/day when coadministered with dolutegravir. Obesity has been linked to lower metformin exposures, and our study aimed to verify the metformin pharmacokinetic exposure in the increasing population of obese WWH. METHODS:We conducted intensive plasma sampling in virally suppressed WWH receiving metformin extended-release 1000 mg once daily with concomitant dolutegravir 50 mg once daily. Dual-energy X-ray absorptiometry was performed to quantify body fat composition. Noncompartmental analysis of metformin and dolutegravir concentrations was performed, and our findings were compared to the reference study. RESULTS:We enrolled 15 participants with a mean body mass index of 45.6 kg/m2. Metformin area under the concentration-time curve over the 24-hour dosing interval (AUC0-24) was 40.9% lower and dolutegravir AUC0-24 was 54.4% lower in obese WWH compared to the reference study. Metformin and dolutegravir clearance were 1.7- and 2.2-fold higher, respectively. Linear regression did not show associations between body fat composition and metformin or dolutegravir exposures. CONCLUSIONS:Limiting metformin to 1000 mg daily is likely to lead to underdosing in obese WWH on dolutegravir. Lower metformin exposure appears to be due to the reduced inhibitory effect of lower dolutegravir concentrations on metformin clearance and increased volume of distribution due to obesity. Our data support the revision of the current maximum dose restriction of metformin in the target population of obese WWH.

Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome. This study investigated the effects of DTG on the trace amine profile in a wistar rat model. A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue. Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels. Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile.

Introduction: Retrograde intrarenal surgery (RIRS) is associated with complications, many of which are related to the intrarenal pressure (IRP). We aim to describe the design of a novel isoprenaline-eluting guidewire ("IsoWire") and present the results from the first in vitro release studies and the first animal studies showing its effect on IRP.Materials and Methods: The IsoWire comprises a Nitinol core surrounded by a stainless-steel wire wound into a tight coil. The grooves created by this coil provided a reservoir for adding a hydrogel coating into which isoprenaline, a beta-agonist, was loaded. Animal studies were performed using a porcine model. For the control, IRP, heart rate (HR), and mean arterial pressure (MAP) were measured continuously for 6 minutes with a standard guidewire in place. For the experiment, the standard hydrophilic guidewire was removed, the IsoWire was inserted into the renal pelvis, and the same parameters were measured.Results: In vitro analysis of the isoprenaline release profile showed that most (63.9 +/- 5.9%) of the loaded drug mass was released in the 1st minute, and almost all of the drug was released in the first 4 minutes exponentially. Porcine studies showed a 25.1% reduction in IRP in the IsoWire that released 10 mu g in the 1st minute; however, there was a marked increase in HR. The average percentage reduction in IRP was 8.95% and 21.3% in the IsoWire that released 5 and 7.5 mu g of isoprenaline, respectively, with no changes in HR or MAP.Conclusions: The IsoWire, which releases 5 and 7.5 mu g of isoprenaline in the 1st minute, appears to be safe and effective in reducing the IRP. Further studies are needed to establish whether the isoprenaline-induced ureteral relaxation will render easier insertion of a ureteral access sheath, reduce IRP during sheathless RIRS, or even promote the practice of sheathless RIRS.

Abstract Background Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether–lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy. Methods Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR–RFLP. Results A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0–2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors. Conclusions The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.

Thiafentanil is a popular opioid agonist that is fully reversed by administering naltrexone. This agonist-antagonist combination is administered to a wide variety of wildlife species for chemical immobilisation, however plasma concentrations for thiafentanil remain unreported. This report describes a method that was developed and validated using human plasma and cross-validated for the analysis of goat plasma. Samples were extracted using a simple protein precipitation and analysed using LC-MS/MS. The assay was validated over the calibration range 4.38 - 1120 ng/mL for thiafentanil and 15.63 - 4000 ng/mL for naltrexone. The mean inter-day accuracies for QCs prepared in human plasma (n = 18) ranged from 94.8 - 103.8 % for thiafentanil and 94.8 - 95.9 % for naltrexone with corresponding precisions of 3.4 - 7.9 % and 2.8 - 11.4 %, respectively. The mean accuracies for QCs prepared in goat plasma (n = 6) ranged from 89.0 - 100.5 % for thiafentanil and 89.0 - 98.0 % for naltrexone with the associated precisions ranging from 7.1 - 11.6 % and 4.8 - 12.3 %, respectively. Both analytes were stable on bench for six hours and for three freeze-thaw cycles. The impact of heat-inactivation, necessary for the inactivation of potential foot-and-mouth disease, on analyte stability, matrix effect and recovery were evaluated, and a correction factor was established to determine the original analyte concentrations. The method was applied to pharmacokinetic samples collected from goats. The use of goats as a model species provides the first insight into the plasma concentrations of thiafentanil.

Introduction: Several complications of retrograde intrarenal surgery have been attributed to inadvertent increases in intrarenal pressure. We recently described the development of an innovative isoprenaline-eluting guidewire (IsoWire). The objective of this study was to investigate the impact of this IsoWire on the intrarenal pressure and evaluate its safety.Materials and Methods: This study was performed in 17 renal units using a porcine model. As controls, the intrarenal pressure, heart rate, and mean arterial pressure were measured for a duration of six minutes with a standard guidewire placed in the renal pelvis. For the experiment, the conventional guidewire was substituted with the IsoWire and the same parameters were measured. Blood samples were taken at one-minute intervals to measure plasma isoprenaline levels. This procedure was repeated on the opposite side.Results: The mean intrarenal pressure reduction was 29% (95% CI: 13%-53%). The mean isoprenaline effect time was 174 seconds. No changes in heart rate (p = .908) or mean arterial pressure (p = .749) were recorded after IsoWire insertion. Plasma isoprenaline levels were below the quantitation threshold. Isoprenaline concentrations in the plasma were below the quantification threshold. Ureteroscopy revealed no ureteral lesions.Conclusions: The IsoWire demonstrated a safe and effective reduction of intrarenal pressure. Additional research is necessary to determine whether ureteral smooth muscle relaxation generated by isoprenaline facilitates easier insertion of a ureteral access sheath, decreases the incidence of ureteral access sheath related ureteral lesions, or even encourage the practice of sheathless retrograde intrarenal surgery.