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Fear of severe adverse reaction (SAR) and reluctance of health care providers to administer intramuscular injections are major contributing factors to poor adherence of benzathine penicillin G (BPG) in the management of rheumatic heart disease (RHD). However, data on the risk of SARs following BPG injections for RHD are relatively limited and inconclusive. Our systematic review and meta-analysis aimed to evaluate the incidence of SARs associated with BPG injections used for secondary prophylaxis of RHD. A systematic literature search of PubMed, Scopus and Web of Science databases was conducted to identify relevant studies reporting adverse reactions following BPG injections in patients with acute rheumatic fever (ARF) and/or RHD. A random effect meta-analysis was performed to estimate the pooled incidence of SARs. Nine studies (eight cohort and one randomized controlled trial), comprising 11,587 participants and > 154,760 BPG injections, were included in the analysis. The pooled incidence of SARs was 9.7 per 10,000 cases (95% CI: 0.1-29.2) and 1.1 per 10,000 BPG injections (95% CI: 0.4-2.2). Six fatal reactions were reported (0.05% of patients and 24% of SARs), all occurring in patients with severe RHD. SARs following BPG injections in patients with ARF or RHD are rare. Our findings highlight the importance of balancing the low rate of SARs against the benefits of BPG in secondary prophylaxis for RHD, particularly in high-risk populations. High-quality longitudinal research and comprehensive adverse reaction reporting are essential to address safety concerns among healthcare providers and patients that impact BPG delivery.

Our objective was to establish and test a machine learning‐based screening process that would be applicable to systematic reviews in pharmaceutical sciences. We used the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, Research type) model, a broad search strategy, and a machine learning tool (Research Screener) to identify relevant references related to y‐site compatibility of 95 intravenous drugs used in neonatal intensive care settings. Two independent reviewers conducted pilot studies, including manual screening and evaluation of Research Screener, and used the kappa‐coefficient for inter‐reviewer reliability. After initial deduplication of the search strategy results, 27 597 references were available for screening. Research Screener excluded 1735 references, including 451 duplicate titles and 1269 reports with no /title, which were manually screened. The remainder (25 862) were subject to the machine learning screening process. All eligible articles for the systematic review were extracted from <10% of the references available for screening. Moderate inter‐reviewer reliability was achieved, with kappa‐coefficient ≥0.75. Overall, 324 references were subject to full‐text reading and 118 were deemed relevant for the systematic review. Our study showed that a broad search strategy to optimize the literature captured for systematic reviews can be efficiently screened by the semi‐automated machine learning tool, Research Screener. Overview of systematic review search, screening and selection process.

Introduction Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control. Methods To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM. Results A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m.sup.2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg.sup.-1) whilst the absorption half-life (t.sub.1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively. Conclusions The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs.

IntroductionRegular intramuscular benzathine penicillin G injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. As the pharmacological correlate of protection remains unknown, it is difficult to recommend changes to this established regimen. Determining the minimum effective penicillin exposure required to prevent Streptococcus pyogenes infection will accelerate development of new long-acting penicillins for RHD prevention as well as inform opportunities to improve existing regimens. The CHIPS trial will address this knowledge gap by directly testing protection afforded by different steady state plasma concentrations of penicillin in an established model of experimental human S. pyogenes pharyngitis.Methods and analysisThis is a double-blinded, placebo-controlled, randomised experimental human infection study. Sixty healthy adult volunteers aged 18–40 years will be recruited and randomised 1:1:1:1:1 to continuous intravenous penicillin infusions targeting five different steady state plasma concentrations of 0 (placebo), 3, 6, 12 and 20 ng/mL via a midline catheter. Each participant’s penicillin pharmacokinetic parameters will be established prior to the challenge, to ensure accurate dosing for the continuous infusion. Following the challenge with a well-characterised strain of S. pyogenes, participants will be observed for up to 6 days for the development of pharyngitis and treated with antibiotics prior to discharge. The primary objective is to determine the minimum effective steady-state plasma penicillin concentration required to prevent experimental pharyngitis. Secondary objectives will explore systemic and mucosal immunoinflammatory responses during pharyngitis, bacterial colonisation dynamics, environmental contamination and qualitative evaluation of the participant experience.Ethics and disseminationEthical approval has been obtained (Bellberry Human Research Ethics Committee). Findings will be reported in peer-reviewed publications and presented at national/international stakeholder forums.Trial registration numberACTRN12621000751875.

An established procedure, including a validated, stability-indicating high-performance liquid chromatography (HPLC) assay was used for evaluating the physical and chemical compatibility of the PTX-drug combinations at room temperature. 3,4,6 Briefly, clear glass vials with impermeable lids were used for each combination of drugs and the respective control solutions: PTX solution and the test drug solution were combined 1:1 in each of the four vials; PTX solution was diluted 1:1 with 0.9% w/v sodium chloride injection (n = 4 vials) as the reference solution for the purposes of visual comparison and HPLC assay, and; The test drug solution was diluted 1:1 with the applicable diluent (n = 4 vials) for the purpose of visual comparison. TABLE 1 Ratio of pentoxifylline (PTX) concentration when combined with the test drug, compared to PTX standard solution (2.5 mg/ml) Drug Test concentration Diluent PTX ratio (%) 95% CI of the ratio Acyclovir (mg/ml) 5 D5W 99.5 98.9‒100.1 Alprostadil (µg/ml) † 10 NS 99.9 99.4‒100.5 Alprostadil (µg/ml) † 20 NS 99.9 99.5‒100.3 Amoxicillin (mg/ml) 100 WfI 95.8 95.0‒96.6 Ampicillin (mg/ml) 100 WfI 96.9 95.6‒98.2 Calcium gluconate (mg/ml) †‡ 100 U 99.7 99.3‒100.0 Cloxacillin (mg/ml) 100 WfI 100.1 99.1‒101.1 Dopamine (mg/ml) 1.6 NS 97.6 95.9‒99.2 Dopamine (mg/ml) 1.6 D5W 99.3 98.7‒100.7 Dopamine (mg/ml) † 7.2 NS 99.2 98.7‒99.7 Dopamine (mg/ml) † 7 D5W 99.2 99.0‒99.4 Epinephrine (µg/ml) † 25 D5W 99.8 99.1‒100.4 Epinephrine (µg/ml) † 50 D5W 99.5 98.8‒100.1 Fentanyl (µg/ml) 5 D5W 100.0 98.7‒101.3 Fentanyl (µg/ml) 25 D5W 99.2 97.4‒101.0 Fentanyl (µg/ml) 50 U 100.1 99.6‒100.6 Fluconazole (mg/ml) ‡ 2 NS 99.4 98.8‒100.1 Furosemide (mg/ml) † 1 NS 100.0 99.7‒100.3 Furosemide (mg/ml) † 1 D5W 99.6 99.2‒100.0 Hydrocortisone (mg/ml) 2 NS 99.2 97.9‒100.5 Ibuprofen lysine (mg/ml) 4 NS 99.3 98.9‒99.8 Ibuprofen lysine (mg/ml) 4 D5W 100.4 99.1‒101.8 Midazolam (µg/ml) 120 D5W 99.4 98.6‒100.2 Midazolam (µg/ml) 120 D10 99.1 98.0‒100.2 Midazolam (µg/ml) 500 D5W 99.8 99.5‒100.1 Midazolam (µg/ml) ‡ 500 D10 99.7 99.5‒99.9 Midazolam (mg/ml) † 1 U 99.7 99.4‒100.1 Midazolam (mg/ml) †§ 1 NS 99.0 97.5‒100.5 Midazolam (mg/ml) †§ 1 D5W 99.8 99.3‒100.4 Milrinone (µg/ml) 200 NS 99.3 98.5‒100.1 Milrinone (µg/ml) 200 D5W 100.0 99.0‒101.0 Milrinone (µg/ml) † 400 NS 100.2 99.2‒101.3 Milrinone (µg/ml) †‡ 400 D5W 100.1 99.7‒100.5 Morphine hydrochloride (µg/ml) 200 NS 99.2 98.8‒99.7 Morphine hydrochloride (µg/ml) 200 D10 97.9 97.2‒98.5 Morphine hydrochloride (µg/ml) † 500 NS 99.9 99.2‒100.6 Morphine hydrochloride (µg/ml) † 500 D5W 99.4 98.8‒100.0 Morphine hydrochloride (µg/ml) † 500 D10 100.3 99.8‒100.7 Morphine sulfate (µg/ml) 200 NS 98.3 97.1‒99.6 Morphine sulfate (µg/ml) ‡ 200 D10 100.4 99.8‒101.0 Morphine sulfate (µg/ml) † 500 NS 100.3 100.0‒100.5 Morphine sulfate (µg/ml) † 500 D5W 100.2 99.8‒100.6 Morphine sulfate (µg/ml) † 500 D10 100.9 99.7‒102.1 Norepinephrine (µg/ml) ‡ 12 D5W 99.7 99.1‒100.2 Norepinephrine (µg/ml) † 64 D5W 100.1 99.5‒100.6 Norepinephrine (µg/ml) 12 NS 99.5 98.3‒100.7 Norepinephrine (µg/ml) † 64 NS 99.3 98.7‒100.0 Phenobarbitone (mg/ml) 20 NS 99.8 99.2‒100.4 Phenobarbitone (mg/ml) 20 D5W 99.9 99.1‒100.7 Piperacillin/tazobactam (mg/ml) 80 D5W 100.2 99.9‒100.5 Piperacillin/tazobactam (mg/ml) 200 WfI 100.5 99.6‒101.5 Results in bold indicate a statistically significant difference, whereby the 95% CI of the ratio did not span 100% (t-test). Abbreviations: CI, confidence interval; D5W, 5% w/v glucose injection; D10, 10% w/v glucose injection; NS, 0.9% w/v sodium chloride injection; PTX, pentoxifylline; U, undiluted; WfI, water for injection. †Duration of mixture contact time = 2 h (contact time for all other combinations = 1 h). ‡n ≥ 8 (all other combinations n = 4). §Midazolam 5 mg/ml diluted with NS/D5W; all other combinations were dilutions of midazolam 1 mg/ml injection. ¶Pentoxifylline injection was diluted in 0.9% w/v sodium chloride injection to a final concentration of 5 mg/ml to combine with the test drug solution. Dilution in 10% w/v glucose or 0.9% w/v sodium chloride showed modest reductions in concentration ratios (1%‒2% compared to control) and most likely presents no clinically significant risk when morphine is co-administered via Y-site with PTX injection for up to 1 h. 3,4 A confounding result in our current study was the unequivocal compatibility of undiluted calcium gluconate injection (100 mg/ml) with PTX injection (Table 1).

Sildenafil is used to treat pulmonary hypertension in neonatal intensive care unit (NICU) settings. As multiple intravenous (IV) medications are co-administered in NICU settings, we sought to investigate the physicochemical compatibility of sildenafil with a range of IV drugs. Sildenafil 600 mcg/mL or 60 mcg/mL was mixed 1:1 with the secondary drug solution to simulate Y-site co-administration procedures. Physical compatibility was evaluated by visual observation against a black and white background and under polarized light for two hours for changes in colour, precipitation, haze and evolution of gas. Chemical compatibility was determined from sildenafil concentrations, using a validated, stability-indicating high-performance liquid chromatography assay. Sildenafil 600 mcg/mL was physicochemically compatible with 29 of the 45 drugs tested at ‘high-end’ clinical concentrations and physically incompatible with 16 drugs and six ‘2-in-1’ parenteral nutrition solutions. Sildenafil 600 mcg/mL was compatible with lower, clinically relevant concentrations of calcium gluconate, heparin and hydrocortisone. Aciclovir, amoxicillin, ampicillin, ibuprofen lysine, indometacin, phenobarbitone and rifampicin were incompatible with sildenafil 600 mcg/mL, however these IV medications were compatible with sildenafil 60 mcg/mL. Sildenafil 600 mcg/mL and 60 mcg/mL were incompatible with amphotericin, flucloxacillin, furosemide, ibuprofen, meropenem and sodium bicarbonate. Sildenafil compatibility with commonly used syringe filters was also investigated. Sildenafil solution was compatible with nylon syringe filters, however, absorption/adsorption loss occurred with polyethersulfone and cellulose ester filters.

Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol.

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5–2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage), although against the late-stage gametocytes, activity is expressed, like other amino-artemisinins, at a prolonged incubation time of 72 h. Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox, and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

Benzathine penicillin G (BPG) is used as first‐line treatment for most forms of syphilis and as secondary prophylaxis against rheumatic heart disease (RHD). Perceptions that poor quality of BPG is linked to reported adverse effects and therapeutic failure may impact syphilis and RHD control programs. Clinical networks and web‐based advertising were used to obtain vials of BPG from a wide range of countries. The quality of BPG was assessed using a high performance liquid chromatography assay capable of detecting relevant impurities and degradation products. Tests for water content, presence of heavy metals and physical characteristics of BPG, including particle size analysis and optical microscopy, also were conducted. Thirty‐five batches of BPG were sourced from 16 countries across 4 WHO regions. All batches passed the US Pharmacopeia requirements for BPG injection (content), with no evidence of breakdown products or other detected contaminants. Water content and heavy metal analysis (n = 11) indicated adherence to regulatory standards and Good Manufacturing Practice. Particle size analysis (n = 20) found two batches with aggregated particles (>400 µm) that were dispersed following sonication. Current batches of BPG were of satisfactory pharmaceutical quality but aggregated particles were found in a modest proportion of samples. Future studies should focus on the physical characteristics of BPG which may contribute to variations in plasma penicillin concentrations an observed needle blockages in clinical practice. Pharmacopeial monographs could be revised to include standards on particle size and crystal morphology of BPG. All 35 batches were of adequate pharmaceutical potency required by the United States pharmacopeial standards. Differences in crystal size between brands may explain variability in clinician experience, providing opportunities to improve manufacturing standards.

The HPLC peak area values obtained with and without filtration were compared and data reported as per cent recovery: %Recovery=100×PTX(filtered)peakareaPTX(unfiltered)peakarea Nylon and polyether sulfone (syringe and inline) filters showed a PTX recovery >98% in all millilitre portions of the filtrate, when PTX was diluted in 0.9% w/v sodium chloride injection (figure 1). [...]our data indicate that PTX injection (5 mg/mL) is compatible with filter membranes commonly used in clinical settings, with <5% absorption/adsorption loss in each of four successive millilitre portions passed through the filters tested in the present study. Contributors All authors contributed to the study design, interpretation of data and manuscript preparation.