Rapid induction of transdermal buprenorphine to subcutaneous extended-release buprenorphine for the treatment of opioid use disorder.

BACKGROUND: Buprenorphine is an effective and safe treatment for opioid use disorder, but the requirement for moderate opioid withdrawal symptoms to emerge prior to initiation is a significant treatment barrier. CASE PRESENTATION: We report on two cases of hospitalized patients with severe, active opioid use disorder, in which we initiated treatment with transdermal buprenorphine over 48 h, followed by the administration of a single dose of sublingual buprenorphine/naloxone and then extended-release subcutaneous buprenorphine. The patients did not experience precipitated withdrawal and only had mild withdrawal symptoms. CONCLUSIONS: This provides preliminary evidence for a rapid induction strategy that may improve tolerability, caregiver burden, and treatment retention as compared to previous induction strategies.

Pharmacokinetics and pharmacodynamics of intravenously and subcutaneously administered pantoprazole in sheep (Ovis aries).

Abomasal ulcers are recognized in sheep of all ages, but research regarding therapeutic interventions is limited. Proton Pump Inhibitors (PPIs) such as pantoprazole, are clinically used with a paucity of evidence regarding efficacy in mature sheep. Intravenous and subcutaneously administered pantoprazole dosed at 1.0 mg/kg in adult sheep will increase the pH of abomasal fluid compared to pre-administration baseline. The objectives were to assess the effect of pantoprazole, after single and multiple administration, on abomasal fluid pH in adult sheep. A third objective was to describe the pharmacokinetic parameters of IV and SC pantoprazole. Four clinically healthy adult Southdown ewes previously fitted with a gastrostomy tube in the abomasum were utilized in this randomized, 2-way cross-over trial. Ewes received pantoprazole (1.0 mg/kg) as a single and 3-dose regimen (every 24 hours). After a 10 day washout period the reverse treatment was applied. Blood for analysis of pantoprazole concentration was collected intermittently for 24 hours, and abomasal fluid pH was measured at intervals for a 96-hour period. The pH of the abomasal fluid was higher in pantoprazole treatments for up to 24 hours after dosing. Following intravenous administration of pantoprazole to study ewes, elimination half-life, volume of distribution, and clearance of pantoprazole was estimated as 3.29 hours, 0.35 L/kg, and 65.26 mL/hr/kg respectively. After subcutaneous dosing, maximum concentration, time to maximum concentration, half-life of elimination, and volume of distribution, were estimated as 2604 ng/mL, 0.55 hours, 2.48 hours, and 0.37 L/kg. Additionally, the bioavailability was estimated as 83.33%. Pantoprazole administered IV or SC may be useful for treatment or prevention of abomasal ulcers in adult sheep.

Vitamin B12 deficiency.

No international treatment standard for B12 deficiency exists. Current practice predominantly relies on more than 50 years old data. Consequently, this review investigates that we still recommend five injections with 1 mg B12 over 10 days followed by maintenance therapy with 1 mg oral B12 daily or injections, of which the interval is guided by symptom relief rather than normalization of biomarkers. Clinical studies are highly warranted and should include formulation and administration of B12. Subcutaneous self-injection may prove cost-effective and benefit an individualized treatment strategy.

Owners' experiences of administering meglumine antimoniate injections to dogs with leishmaniosis: An online questionnaire study.

BACKGROUND: This study examined the experiences of owners of dogs with leishmaniosis who treated their dogs with daily subcutaneous meglumine antimoniate injections. The owners' perceived ease of administering the injections, the occurrence of problems and the effects on the owners and on the dog‒owner bond were evaluated. METHODS: Dogs prescribed meglumine antimoniate as a treatment for leishmaniosis were identified using the database of the veterinary pharmacy of the Faculty of Veterinary Medicine, Utrecht University. An online questionnaire was sent to the owners of these dogs to evaluate the perceived ease of administering the injections, the occurrence of problems and the effects on the owner and the dog-owner bond. RESULTS: Responses were received from 64 dog owners. Most respondents (78%) reported that administering the injections was not difficult. Pain or the development of nodules at the injection site was reported in 50% and 40% of the dogs, respectively. Polyuria was reported in 44% of the dogs. Some owners reported that administering the injections had a negative impact on their psychological wellbeing (20%), and some would have liked more veterinary support (11%). LIMITATIONS: Some questions were answered by a limited number of people, and their responses may not be representative. CONCLUSION: Dog owners remain highly motivated to persevere with meglumine antimoniate treatment and are willing to administer the injections themselves. The availability of active support when needed during the therapy cycle may further improve their acceptance of and confidence in giving the injections.

Anti-Drug Antibody Incidence Comparison of Therapeutic Proteins Administered Via Subcutaneous vs. Intravenous Route.

Subcutaneous (SC) administration of therapeutic proteins is perceived to pose higher risk of immunogenicity when compared with intravenous (IV) route of administration (RoA). However, systematic evaluations of clinical data to support this claim are lacking. This meta-analysis was conducted to compare the immunogenicity of the same therapeutic protein by IV and SC RoA. Anti-drug antibody (ADA) data and controlling variables for 7 therapeutic proteins administered by both IV and SC routes across 48 treatment groups were analyzed. RoA was the primary independent variable of interest while therapeutic protein, patient population, adjusted dose, and number of ADA samples were controlling variables. Analysis of variance was used to compare the ADA incidence between IV and SC RoA, while accounting for controlling variables and potential interactions. Subsequently, 10 additional therapeutic proteins with ADA data published for both IV and SC administration were added to the above 7 therapeutic proteins and were evaluated for ADA incidence. RoA had no statistically significant effect on ADA incidence for the initial dataset of 7 therapeutic proteins (p = 0.55). The only variable with a significant effect on ADA incidence was the therapeutic protein. None of the other controlling variables, including their interactions with RoA, was significant. When all data from the 17 therapeutic proteins were pooled, there was no statistically significant effect of RoA on ADA incidence (p = 0.81). In conclusion, there is no significant difference in ADA incidence between the IV and SC RoA, based on analysis of clinical ADA data from 17 therapeutic proteins.

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Safety and Efficacy of the Modified Vaccinia Ankara-Bavaria Nordic Vaccine Against Mpox in the Real World: Systematic Review and Meta-Analysis.

In May 2022, mpox began to spread worldwide, posing a serious threat to human public health. Modified Vaccinia Ankara-Bavaria Nordic (MVA-BN) is a live attenuated orthopoxvirus vaccine that has been authorized by the U.S. Food and Drug Administration as the vaccine of choice for the prevention of mpox. In this study, we conducted a meta-analysis of all currently published literature on the efficacy and safety of the MVA-BN vaccine in the real world, showing that the MVA-BN vaccine is effective and safe, with efficacy of up to 75% with a single dose and up to 80% with a two-dose vaccine. Meanwhile, we found that subcutaneous injection has lower local and systemic adverse events than intradermal injection, regardless of single- or two-dose vaccination, and subcutaneous injection is better tolerated in children, the elderly, or people with underlying medical conditions. These results have important reference value for clinical practice.

Subcutaneous administration of Stattic alleviates neuropathic pain by relieving inflammation in a mouse model of postherpetic neuralgia.

Stattic, a commercial inhibitor of STAT3, can drive the development of neuropathic pain. Exploring the connection between Stattic and JAK1/STAT3 signaling may facilitate the understanding of neuropathic pain caused by postherpetic neuralgia (PHN). In the current study, as crucial regulators of inflammation, STAT3 and its associated JAK1/STAT3 pathway were found to be upregulated and activated in the L4-L6 dorsal root ganglion (DRG) of mice in response to resiniferatoxin (RTX)-induced PHN, while subcutaneous administration of Stattic was found to downregulate STAT3 expression and phosphorylation in a PHN model. Stattic administration further attenuated hypersensitivity to mechanical and thermal stimuli in PHN mice, and alleviated inflammation and cell death in the L4-L6 DRG of mice. Overexpression of STAT3 via microinjection of a lentiviral-STAT3 overexpression vector reversed the abnormal decrease of STAT3 at both the mRNA and protein levels in the L4-6 DRGs of PHN mice and significantly promoted hypersensitivity to mechanical stimuli in the mice. Collectively, we found that subcutaneous static administration alleviated RTX-induced neuropathic pain by deactivating JAK1/STAT3 in mice.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Prediction of subcutaneous drug absorption - Development of novel simulated interstitial fluid media for predictive subcutaneous in vitro assays.

Media that mimic physiological fluids at the site of administration have proven to be valuable in vitro tools for predicting in vivo drug release, particularly for routes of administration where animal studies cannot accurately predict human performance. The objective of the present study was to develop simulated interstitial fluids (SISFs) that mimic the major components and physicochemical properties of subcutaneous interstitial fluids (ISFs) from preclinical species and humans, but that can be easily prepared in the laboratory and used in in vitro experiments to estimate in vivo drug release and absorption of subcutaneously administered formulations. Based on data from a previous characterization study of ISFs from different species, two media were developed: a simulated mouse-rat ISF and a simulated human-monkey ISF. The novel SISFs were used in initial in vitro diffusion studies with a commercial injectable preparation of liraglutide. Although the in vitro model used for this purpose still requires significant refinement, these two new media will undoubtedly contribute to a better understanding of the in vivo performance of subcutaneous injectables in different species and will help to reduce the number of unnecessary in vivo experiments in preclinical species by implementation in predictive in vitro models.

Clinical trial evaluating apomorphine oromucosal solution in Parkinson's disease patients.

Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.

Lymphatic uptake of the lipidated and non-lipidated GLP-1 agonists liraglutide and exenatide is similar in rats.

Peptides, despite their therapeutic potential, face challenges with undesirable pharmacokinetic (PK) properties and biodistribution, including poor oral absorption and cellular uptake, and short plasma elimination half-lives. Lipidation of peptides is a common strategy to improve their physicochemical and PK properties, making them viable drug candidates. For example, the plasma half-life of peptides has been extended via conjugation to lipids that are proposed to promote binding to serum albumin and thus protect against rapid clearance. Recent work has shown that lipid conjugation to oligodeoxynucleotides, polymers and small molecule drugs results in association not only with albumin, but also with lipoproteins, resulting in half-life prolongation and transport from administration sites via the lymphatics. Enhancing delivery into the lymph increases the efficacy of vaccines and therapeutics with lymphatic targets such as immunotherapies. In this study, the plasma PK, lymphatic uptake, and bioavailability of the glucagon-like peptide-1 (GLP-1) receptor agonist peptides, liraglutide (lipidated) and exenatide (non-lipidated), were investigated following subcutaneous (SC) administration to rats. As expected, liraglutide displayed an apparent prolonged plasma half-life (9.1 versus 1 h), delayed peak plasma concentrations and lower bioavailability (∼10 % versus ∼100 %) compared to exenatide after SC administration. The lymphatic uptake of both peptides was relatively low (<0.5 % of the dose) although lymph to plasma concentration ratios were greater than one for several early timepoints suggesting some direct uptake into lymph. The low lymphatic uptake may be due to the nature of the conjugated lipid (a single-chain C16 palmitic acid in liraglutide) but suggests that other peptides with similar lipid conjugations may also have relatively modest lymphatic uptake. If delivery to the lymph is desired, conjugation to more lipophilic moieties with higher albumin and/or lipoprotein binding efficiencies, such as diacylglycerols, may be appropriate.

[Prevalence of hypophosphatemia in children with diabetic ketoacidosis and treatment with subcutaneous regular insulin. Observational study]. / Prevalencia de Hipofosfatemia en niños con cetoacidosis diabética y tratamiento con insulina regular subcutánea. Estudio observacional.

Diabetic ketoacidosis (DKA) is one of the most serious complications of type 1 diabetes mellitus. Its treatment requires fluid and electrolyte replacement and insulin. Hypophosphatemia as a complication of treatment has been scarcely evaluated. OBJECTIVES: To estimate the incidence of hypophosphatemia in children with DKA, treated with subcutaneous regular insulin (IRS), and to explore factors associated with this complication. PATIENTS AND METHOD: Prospective, observational study. Patients diagnosed with DKA hospitalized in the general care ward were included. Data on phosphatemia, glycemia, acid-base status, and IRS amount (U/kg) received were recorded at baseline and after 24 h of treatment. Hypophosphatemia was defined as values below 2.5 mg/dl. The correlation between initial phosphate and at 24 h of treatment was evaluated; the incidence of hypophosphatemia at 24 h was expressed as a percentage of the total number of patients. RESULTS: 30 patients were included, 15 were female, mean age 11.4 ± 3.2 years. At 24 h of treatment with IRS, 36.7% (95%CI 22-55%) presented hypophosphatemia, mean value 1.9 ± 1.5 mg/dl. Initial bicarbonate < 10 mmol/L acted as a predictor of hypophosphatemia (OR 7.5; 95%CI 1.4-39.8%; p = 0.01). No patient required intravenous phosphate correction, and no associated clinical complications were observed. CONCLUSION: In the group studied, the incidence of hypophosphatemia reached 36.7% at 24 hours of treatment. Initial bicarbonate lower than 10 mmol/L was significantly associated with hypophosphatemia. No complications associated with hypophosphatemia were observed.

Safety, tolerability, and pharmacokinetics of single- and multiple-ascending doses of olamkicept: Results from randomized, placebo-controlled, first-in-human phase I trials.

Olamkicept selectively inhibits the cytokine interleukin-6 (IL-6) trans-signaling pathway without blocking the classic pathway and is a promising immunoregulatory therapy for inflammatory bowel disease (IBD). These first-in-human, randomized, placebo-controlled, single- (SAD) and multiple-ascending dose (MAD) trials evaluated olamkicept safety, tolerability, pharmacokinetic, and pharmacodynamic characteristics. Doses tested in the SAD trial included seven single intravenous doses (0.75, 7.5, 75, 150, 300, 600, and 750 mg) and one subcutaneous (SC) dose (60 mg) given to healthy subjects (N = 64), and three intravenous doses (75 mg, 300 mg, and 750 mg) given to patients with Crohn's disease (CD; N = 24). Doses tested in the MAD trial included multiple intravenous doses (75, 300, and 600 mg once weekly for 4 weeks) given to healthy subjects (N = 24). No severe or serious treatment-emergent adverse events (TEAEs) were recorded. The most common TEAEs were headache, nasopharyngitis, and myalgia in the SAD trial, and diarrhea, headache, and cough in the MAD trial. Infusion-related reactions occurred in one and two subjects in the SAD and MAD trial, respectively, leading to treatment discontinuation in the MAD trial. Olamkicept showed dose-independent pharmacokinetics after single and multiple administrations, and there was no major difference in systemic exposure between healthy subjects and patients with CD. Complete target engagement (inhibition of phosphorylation of signal transducer and activator of transcription-3) was achieved in blood around or above olamkicept serum concentrations of 1-5 µg/mL. Overall, these results suggest that olamkicept is safe and well-tolerated in healthy subjects and patients with CD after single intravenous/SC and multiple intravenous administrations.

Tirzepatide 5, 10 and 15 mg versus injectable semaglutide 0.5 mg for the treatment of type 2 diabetes: An adjusted indirect treatment comparison.

AIMS: To compare the efficacy and safety of tirzepatide 5, 10 and 15 mg with subcutaneous semaglutide 0.5 mg as second-line treatment for adults with type 2 diabetes mellitus, after metformin monotherapy, using adjusted indirect treatment comparisons (aITCs). METHODS: The aITCs were performed using the Bucher method to compare the relative efficacy and safety of tirzepatide 5, 10 and 15 mg versus semaglutide 0.5 mg via a common comparator (subcutaneous semaglutide 1.0 mg) based on trial results from SURPASS-2 (NCT03987919) and SUSTAIN7 (NCT02648204). RESULTS: All tirzepatide doses showed statistically significantly greater reductions in glycated haemoglobin, body weight and body mass index from baseline to week 40, with a comparable adverse event (AE) profile and no statistically significant differences in the odds of gastrointestinal AEs versus semaglutide 0.5 mg. Furthermore, all tirzepatide doses showed greater odds of patients achieving HbA1c targets of ≤ 6.5 % (≤48 mmol/mol) and < 7.0 % (<53 mmol/mol) and weight loss targets of ≥ 5 % and ≥ 10 %, versus semaglutide 0.5 mg. CONCLUSIONS: In these aITCs, glycated haemoglobin and weight reductions were significantly greater for all tirzepatide doses versus semaglutide 0.5 mg with a comparable AE profile. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

"Hurts less, lasts longer"; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand.

BACKGROUND: Four-weekly intramuscular (IM) benzathine penicillin G (BPG) injections to prevent acute rheumatic fever (ARF) progression have remained unchanged since 1955. A Phase-I trial in healthy volunteers demonstrated the safety and tolerability of high-dose subcutaneous infusions of BPG which resulted in a much longer effective penicillin exposure, and fewer injections. Here we describe the experiences of young people living with ARF participating in a Phase-II trial of SubCutaneous Injections of BPG (SCIP). METHODOLOGY: Participants (n = 20) attended a clinic in Wellington, New Zealand (NZ). After a physical examination, participants received 2% lignocaine followed by 13.8mL to 20.7mL of BPG (Bicillin-LA®; determined by weight), into the abdominal subcutaneous tissue. A Kaupapa Maori consistent methodology was used to explore experiences of SCIP, through semi-structured interviews and observations taken during/after the injection, and on days 28 and 70. All interviews were recorded, transcribed verbatim, and thematically analysed. PRINCIPAL FINDINGS: Low levels of pain were reported on needle insertion, during and following the injection. Some participants experienced discomfort and bruising on days one and two post dose; however, the pain was reported to be less severe than their usual IM BPG. Participants were 'relieved' to only need injections quarterly and the majority (95%) reported a preference for SCIP over IM BPG. CONCLUSIONS: Participants preferred SCIP over their usual regimen, reporting less pain and a preference for the longer time gap between treatments. Recommending SCIP as standard of care for most patients needing long-term prophylaxis has the potential to transform secondary prophylaxis of ARF/RHD in NZ and globally.

heredERA Breast Cancer: a phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally advanced or metastatic breast cancer.

BACKGROUND: HER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC. First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I-II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression. METHODS: This phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes. DISCUSSION: heredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). SPONSOR: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

A single subcutaneous dose of eprinomectin (Eprecis®) is effective against common gastrointestinal nematodes and lungworms in experimentally infected lactating goats.

BACKGROUND: The health and productivity of dairy goats continue to be impacted by gastrointestinal nematodes (GIN) and lungworms (LW). Eprinomectin (EPN) is frequently selected for treatment because it is generally effective and does not require a milk withdrawal period. However, some factors, such as lactation, can have an impact on EPN pharmacokinetics and potentially its efficacy. To evaluate whether this can alter the efficacy of Eprecis® 2%, an eprinomectin injectable solution, a study was performed in lactating goats using the dose currently registered in cattle, sheep and goats (0.2 mg/kg). METHODS: This study was a blinded, randomized, controlled trial performed according to the VICH guidelines. Eighteen (18) worm-free lactating goats were included and experimentally challenged on day 28 with a mixed culture of infective gastrointestinal and lung nematode larvae (Haemonchus contortus, Trichostrongylus colubriformis, Teladorsagia circumcincta, Dictyocaulus filaria). At D-1, fecal samples were collected to confirm patent infection in all animals. On D0, the goats were randomly allocated into two groups of nine goats; group 1 was treated with Eprecis® 2% at 0.2 mg/kg BW by subcutaneous injection, while group 2 remained untreated. Fecal samples for egg counts were collected from all animals on days 3, 5, 7, 9, 11 and 14. On D14, all goats were killed, and the abomasum, small intestine and lungs were removed, processed and subsampled to record the number and species of worms. RESULTS: The treatment was well tolerated. After treatment, the arithmetic mean FEC decreased in the treated group and remained < 5 EPG until the end of the study, while the arithmetic mean FEC in the control group remained > 849.0 EPG. At D14, goats in the treated group had very limited or zero total worm counts, whereas all animals from the control group had a high worm burden. The measured efficacy was 100.0% against H. contortus and T. colubriformis, 99.9% against T. circumcincta and 98.0% against D. filaria. CONCLUSIONS: Eprinomectin (Eprecis®, 20 mg/ml), administered at the label dose (0.2 mg/kg), is highly effective against gastrointestinal nematodes and lungworms in lactating goats.

Analysis of factors influencing target PASI responses and side effects of methotrexate monotherapy in plaque psoriasis: a multicenter study of 1521 patients.

Methotrexate (MTX) is commonly used as first-line systemic treatment agent in psoriasis. We aimed to evaluate the clinical characteristics and treatment responses of patients with psoriasis undergoing MTX monotherapy. Data from adult patients with plaque psoriasis who received MTX monotherapy for at least 3 months between April 2012 and April 2022 were retrospectively evaluated in 19 tertiary care centers. Our study included 722 female and 799 male patients, a total of 1521 participants. The average age of the patients was 44.3 ± 15.5 years. Mode of treatment was oral in 20.4% of patients while in 79.4% it was subcutaneous. The median treatment duration was 8 months (IQR = 5-15). The median weekly dose was 15 mg (IQR = 11-15). 1448 (95.2%) patients were taking folic acid supplementation. At week 12, 16.3% of the patients achieved PASI (Psoriasis Area and Severity Index) 90 response while at week 24, 37.3% achieved it. Logistic regression analysis for week 12 identified the following independent factors affecting PASI 90 achievement positively: median weekly MTX dose ≤ 15 mg (P = 0.011), subcutaneous administration (P = 0.005), no prior systemic treatment (< 0.001) and folic acid use (0.021). In logistic regression analysis for week 24; median weekly MTX dose ≤ 15 mg (P = 0.001), baseline PASI ≥ 10 (P < 0.001), no prior systemic treatment (P < 0.004), folic acid use (P = 0.001) and absence of comorbidities (P = 0.009) were determined as independent factors affecting the achievement of PASI 90. Adverse effects were observed in 38.8% of the patients, with nausea/vomiting (23.9%) and transaminase elevation (13%) being the most common. The most common reasons for interruptions (15.3%) and discontinuations (27.1%) of the treatment were patient related individual factors. The use of MTX as the first systemic treatment agent, at doses ≤ 15 mg/week and concurrent folic acid application are positive predictive factors for achieving the target PASI response both at weeks 12 and 24. In our study, which is one of the most comprehensive studies on MTX treatment in psoriasis, we observed that MTX is an effective and safe treatment option.

Effect of needle-free injection on psychological insulin resistance and insulin dosage in patients with type 2 diabetes.

Background and objective: Psychological insulin resistance (PIR), which refers to the reluctance of diabetic patients to use insulin, is a frequently encountered clinical issue. Needle-free injection (NFI) offers advantages in terms of expediting insulin absorption and mitigating adverse reactions related to injection. To evaluate the effects of subcutaneous injection of insulin aspart 30 with NFI on PIR and insulin dosage in patients with type 2 diabetes mellitus (T2DM). Methods: Sixty-four patients with T2DM participated in this randomized, prospective, open, crossover study. Insulin aspart 30 was administered subcutaneously to each subject via QS-P NFI and Novo Pen 5 (NP) successively. The effects of NFI on PIR were analyzed. Differences in insulin dosage, glycemic variability, and injection safety were compared at similar levels of glycemic control. Results: After the administration of NFI, the insulin treatment attitude scale score decreased (53.7 ± 7.3 vs. 58.9 ± 10.7, p<0.001), the insulin treatment adherence questionnaire score increased (46.3 ± 4.9 vs. 43.8 ± 7.1, p<0.001), and the insulin treatment satisfaction questionnaire score increased (66.6 ± 10.5 vs. 62.4 ± 16.5, p<0.001). At the same blood glucose level, NFI required a smaller dosage of insulin aspart 30 compared with that of NP (30.42 ± 8.70 vs. 33.66 ± 9.13 U/d, p<0.001). There were no differences in glycemic variability indices (standard deviation, mean amplitude of glycemic excursion or coefficient of variation) between the two injection methods. Compared with NP, NFI did not increase the incidence of hypoglycemia (17.2% vs. 14.1%, p=0.774), and it decreased the incidence of induration (4.7% vs. 23.4%, p=0.002) and leakage (6.3% vs. 20.3%, p=0.022) while decreasing the pain visual analog scale score (2.30 ± 1.58 vs. 3.11 ± 1.40, p<0.001). Conclusion: NFI can improve PIR in patients with T2DM and be used with a smaller dose of insulin aspart 30 while maintaining the same hypoglycemic effect. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2400083658.