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Clinical Therapeutics May 2024Glucophage (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Glucophage (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShield sustained-release formulation tablet of Glucophage has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShield sustained-release formulations of metformin, Glucophage (GXR 500 mg), from Europe and the United States.
METHODS
Data from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC, C, and AUC.
FINDINGS
In all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151-1.0778) for AUC to 1.1344 (90% CI, 1.0711-1.2014) for C; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings.
IMPLICATIONS
Bioequivalence was determined between sustained-release formulations of Glucophage from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of Glucophage XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites.
Topics: Therapeutic Equivalency; Metformin; Humans; Delayed-Action Preparations; Hypoglycemic Agents; Female; Male; Cross-Over Studies; Adult; United States; Tablets; Europe; Young Adult; Area Under Curve; Middle Aged; Administration, Oral; Fasting
PubMed: 38688745
DOI: 10.1016/j.clinthera.2024.03.011 -
Lupus Science & Medicine Apr 2024Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability...
OBJECTIVE
Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients.
METHODS
We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses.
RESULTS
For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements.
CONCLUSIONS
We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy.
Topics: Hydroxychloroquine; Humans; Medication Adherence; Monte Carlo Method; Antirheumatic Agents; Lupus Erythematosus, Systemic; Computer Simulation; Models, Biological
PubMed: 38688714
DOI: 10.1136/lupus-2023-001090 -
General and Comparative Endocrinology Aug 2024Estrogen receptors (ERs) are thought to be the ancestor of all steroid receptors and are present in most lophotrochozoans studied to date, including molluscs, annelids,... (Review)
Review
Estrogen receptors (ERs) are thought to be the ancestor of all steroid receptors and are present in most lophotrochozoans studied to date, including molluscs, annelids, and rotifers. A number of studies have investigated the functional role of estrogen receptors in invertebrate species, although most are in molluscs, where the receptor is constitutively active. In vitro experiments provided evidence for ligand-activated estrogen receptors in annelids, raising important questions about the role of estrogen signalling in lophotrochozoan lineages. Here, we review the concordant and discordant evidence of estradiol receptor signalling in lophotrochozoans, with a focus on annelids and rotifers. We explore the de novo synthesis of estrogens, the evolution and expression of estrogen receptors, and physiological responses to activation of estrogen receptors in the lophotrochozoan phyla Annelida and Rotifera. Key data are missing to determine if de novo biosynthesis of estradiol in non-molluscan lophotrochozoans is likely. For example, an ortholog for the CYP11 gene is present, but confirmation of substrate conversion and measured tissue products is lacking. Orthologs CYP17 and CYP19 are lacking, yet intermediates or products (e.g. estradiol) in tissues have been measured. Estrogen receptors are present in multiple species, and for a limited number, in vitro data show agonist binding of estradiol and/or transcriptional activation. The expression patterns of the lophotrochozoan ERs suggest developmental, reproductive, and digestive roles but are highly species dependent. E exposures suggest that lophotrochozoan ERs may play a role in reproduction, but no strong dose-response relationship has been established. Therefore, we expect most lophotrochozoan species, outside of perhaps platyhelminths, to have an ER but their physiological role remains elusive. Mining genomes for orthologs gene families responsible for steroidogenesis, coupled with in vitro and in vivo studies of the steroid pathway are needed to better assess whether lophotrochozoans are capable of estradiol biosynthesis. One major challenge is that much of the data are divided across a diversity of species. We propose that the polychaetes Capitella teleta or Platyneris dumerilii, and rotifer Brachionus manjavacas may be strong species choices for studies of estrogen receptor signalling, because of available genomic data, established laboratory culture techniques, and gene knockout potential.
Topics: Animals; Signal Transduction; Receptors, Estradiol; Annelida; Receptors, Estrogen; Rotifera; Estradiol
PubMed: 38677339
DOI: 10.1016/j.ygcen.2024.114519 -
Trauma Surgery & Acute Care Open 2024Venous thromboembolism (VTE) risk reduction strategies include early initiation of chemoprophylaxis, reducing missed doses, weight-based dosing and dose adjustment using...
OBJECTIVE
Venous thromboembolism (VTE) risk reduction strategies include early initiation of chemoprophylaxis, reducing missed doses, weight-based dosing and dose adjustment using anti-Xa levels. We hypothesized that time to initiation of chemoprophylaxis would be the strongest modifiable risk for VTE, even after adjusting for competing risk factors.
METHODS
A prospectively maintained trauma registry was queried for patients admitted July 2017-October 2021 who were 18 years and older and received emergency release blood products. Patients with deep vein thrombosis or pulmonary embolism (VTE) were compared to those without (no VTE). Door-to-prophylaxis was defined as time from hospital arrival to first dose of VTE chemoprophylaxis (hours). Univariate and multivariate analyses were then performed between the two groups.
RESULTS
2047 patients met inclusion (106 VTE, 1941 no VTE). There were no differences in baseline or demographic data. VTE patients had higher injury severity score (29 vs 24), more evidence of shock by arrival lactate (4.6 vs 3.9) and received more post-ED transfusions (8 vs 2 units); all p<0.05. While there was no difference in need for enoxaparin dose adjustment or missed doses, door-to-prophylaxis time was longer in the VTE group (35 vs 25 hours; p=0.009). On multivariate logistic regression analysis, every hour delay from time of arrival increased likelihood of VTE by 1.5% (OR 1.015, 95% CI 1.004 to 1.023, p=0.004).
CONCLUSION
The current retrospective study of severely injured patients with trauma who required emergency release blood products found that increased door-to-prophylaxis time was significantly associated with an increased likelihood for VTE. Chemoprophylaxis initiation is one of the few modifiable risk factors available to combat VTE, therefore early initiation is paramount. Similar to door-to-balloon time in treating myocardial infarction and door-to-tPA time in stroke, "door-to-prophylaxis time" should be considered as a hospital metric for prevention of VTE in trauma.
LEVEL OF EVIDENCE
Level III, retrospective study with up to two negative criteria.
PubMed: 38666014
DOI: 10.1136/tsaco-2023-001297 -
JMIR Formative Research Apr 2024In Denmark, outpatient follow-up for patients with chronic kidney disease (CKD) is changing from in-hospital visits toward more remote health care delivery. The nonuse...
BACKGROUND
In Denmark, outpatient follow-up for patients with chronic kidney disease (CKD) is changing from in-hospital visits toward more remote health care delivery. The nonuse of remote patient-reported outcomes (PROs) is a well-known challenge, and it can be difficult to explain which mechanisms of interventions influence the outcome. Process evaluation may, therefore, be used to answer important questions on how and why interventions work, aiming to enhance the implications for clinical practice.
OBJECTIVE
This study aimed to provide insight into the intervention process by evaluating (1) the representativity of the study population, (2) patient and physician use patterns, (3) patient adherence to the intervention, and (4) clinical engagement.
METHODS
A process evaluation determining the reach, dose, fidelity, and clinical engagement was carried out, alongside a multicenter randomized controlled trial (RCT). We developed and implemented an intervention using PRO measures to monitor outpatients remotely. Data were collected for the PRO intervention arms in the RCT from 4 sources: (1) PRO data from the participants to determine personal factors, (2) the web-based PRO system to identify key usage intervention patterns, (3) medical records to identify clinical factors relating to the use of the intervention, and (4) semistructured interviews conducted with involved physicians.
RESULTS
Of the 320 patients invited, 152 (47.5%) accepted to participate. The study population reflected the target population. The mean adherence rate to the PRO intervention arms was 82% (95% CI 76-87). The questionnaire response rate was 539/544 (99.1%). A minority of 13 (12.9%) of 101 patients needed assistance to complete study procedures. Physicians assessed 477/539 (88.5%) of the questionnaires. Contact was established in 417/539 (77.4%) of the cases, and 122/539 (22.6%) of the patients did not have contact. Physicians initiated 288/417 (69.1%) and patients requested 129/417 (30.9%) of all the contacts. The primary causes of contact were clinical data (242/417, 58%), PRO data (92/417, 22.1%), and medication concerns and precautionary reasons (83/417, 19.9%). Physicians found the use of PRO measures in remote follow-up beneficial for assessing the patient's health. The inclusion of self-reported clinical data in the questionnaire motivated physicians to assess patient responses. However, some barriers were emphasized, such as loss of a personal relationship with the patient and the risk of missing important symptoms in the absence of a face-to-face assessment.
CONCLUSIONS
This study demonstrates the importance and practical use of remote monitoring among patients with CKD. Overall, the intervention was implemented as intended. We observed high patient adherence rates, and the physicians managed most questionnaires. Some physicians worried that distance from the patients made it unfeasible to use their "clinical glance," posing a potential risk of overlooking crucial patients' symptoms. These findings underscore key considerations for the implementation of remote follow-up. Introducing a hybrid approach combining remote and face-to-face consultations may address these concerns.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03847766; https://clinicaltrials.gov/study/NCT03847766.
PubMed: 38656781
DOI: 10.2196/48173 -
BMC Primary Care Apr 2024The purpose of this study was to understand the healthcare provider (HCP) perspective on the extent of suboptimal insulin dosing in people with diabetes (PwD), as well...
BACKGROUND
The purpose of this study was to understand the healthcare provider (HCP) perspective on the extent of suboptimal insulin dosing in people with diabetes (PwD), as well as specific challenges and solutions to insulin management.
METHODS
An online survey of general practitioners and specialists (N = 640) who treat PwD in Germany, Spain, the United Kingdom, and the United States was conducted. Responses regarding HCP background and their patients, HCP perceptions of suboptimal insulin use, and challenges associated with optimal insulin use were collected. Categorical summary statistics were presented.
RESULTS
Overall, for type 1 diabetes (T1D) and type 2 diabetes (T2D), most physicians indicated < 30% of PwD missed or skipped a bolus insulin dose in the last 30 days (T1D: 83.0%; T2D: 74.1%). The top 3 reasons (other than skipping a meal) HCPs believed caused the PwD to miss or skip insulin doses included they "forgot," (bolus: 75.0%; basal: 67.5%) "were too busy/distracted," (bolus: 58.8%; basal: 48.3%), and "were out of their normal routine" (bolus: 57.8%; basal: 48.6%). HCPs reported similar reasons that they believed caused PwD to mistime insulin doses. Digital technology and improved HCP-PwD communication were potential solutions identified by HCPs to optimize insulin dosing in PwD.
CONCLUSIONS
Other studies have shown that PwD frequently experience suboptimal insulin dosing. Conversely, results from this study showed that HCPs believe suboptimal insulin dosing among PwD is limited in frequency. While no direct comparisons were made in this study, this apparent discrepancy could lead to difficulties in HCPs giving PwD the best advice on optimal insulin management. Approaches such as improving the objectivity of dose measurements for both PwD and HCPs may improve associated communications and help reduce suboptimal insulin dosing, thus enhancing treatment outcomes.
Topics: Humans; Diabetes Mellitus, Type 1; Insulin; Diabetes Mellitus, Type 2; Cross-Sectional Studies; Hypoglycemic Agents; Male; Female; Middle Aged; Adult; Practice Patterns, Physicians'; Surveys and Questionnaires; Health Personnel; Attitude of Health Personnel
PubMed: 38649812
DOI: 10.1186/s12875-024-02390-9 -
Trials Apr 2024The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population....
BACKGROUND
The World Health Organization recommends universal iron supplementation for children aged 6-23 months in countries where anaemia is seen in over 40% of the population. Conventional ferrous salts have low efficacy due to low oral absorption in children with inflammation. Haem iron is more bioavailable, and its absorption may not be decreased by inflammation. This study aims to compare daily supplementation with haem iron versus ferrous sulphate on haemoglobin concentration and serum ferritin concentration after 12 weeks of supplementation.
METHODS
This will be a two-arm, randomised controlled trial. Gambian children aged 6-12 months with anaemia will be recruited within a predefined geographical area and recruited by trained field workers. Eligible participants will be individually randomised using a 1:1 ratio within permuted blocks to daily supplementation for 12 weeks with either 10.0 mg of elemental iron as haem or ferrous sulphate. Safety outcomes such as diarrhoea and infection-related adverse events will be assessed daily by the clinical team (see Bah et al. Additional file 4_Adverse event eCRF). Linear regression will be used to analyse continuous outcomes, with log transformation to normalise residuals as needed. Binary outcomes will be analysed by binomial regression or logistic regression, Primary analysis will be by modified intention-to-treat (i.e., those randomised and who ingested at least one supplement dose of iron), with multiple imputations to replace missing data. Effect estimates will be adjusted for baseline covariates (C-reactive protein, alpha-1-acid glycoprotein, haemoglobin, ferritin, soluble transferrin receptor).
DISCUSSION
This study will determine if therapeutic supplementation with haem iron is more efficacious than with conventional ferrous sulphate in enhancing haemoglobin and ferritin concentrations in anaemic children aged 6-12 months.
TRIAL REGISTRATION
Pan African Clinical Trial Registry PACTR202210523178727.
Topics: Child; Humans; Iron; Anemia, Iron-Deficiency; Salts; Gambia; Ferrous Compounds; Ferritins; Anemia; Hemoglobins; Dietary Supplements; Inflammation; Heme; Randomized Controlled Trials as Topic
PubMed: 38641845
DOI: 10.1186/s13063-024-08101-0 -
Health Science Reports Apr 2024Due to the concern about the side effects of chemical drugs and their ineffectiveness, the use of natural compounds as alternatives or complementary therapies has...
BACKGROUND AND AIM
Due to the concern about the side effects of chemical drugs and their ineffectiveness, the use of natural compounds as alternatives or complementary therapies has received increasing attention. The purpose of this study was to investigate the effect of oil on the outcome of missed abortion.
METHODS
In this double-blind clinical trial, 70 nulliparous pregnant women referred to Hajar Hospital and Imam Ali clinics of Shahrekord and had missed abortion before the 12-week gestational age were selected and randomly divided into two interventions and control groups. The intervention group received 5 g of oil alone daily for up to 3 days and the control group received a placebo. In case of nonresponse, 3 days after the last dose of medication or placebo, 800 μg of misoprostol (vaginal) were used. Data were analyzed by SPSS software. The chi-square test, Fisher's exact test, independent -test and paired -test were used for analytical statistics.
RESULTS
According to the results, 18 cases (51.4%) in the intervention group and seven cases (20%) in the control group showed complete evacuation of uterine contents which had a significant difference ( < 0.05). The frequency of vagina physical examination and type of hemorrhage did not show any significant difference between the two groups before and after the intervention. After the intervention, human chorionic gonadotropin (HCG) was significantly decreased in the intervention group but did not change in the control group ( < 0.05). The frequency of adverse events in the intervention group was three (8.6%) and in the control group was one (2.9%) which had no significant difference.
CONCLUSION
improves the outcome of missed abortion by reducing HCG and facilitating cervix dilatation and delivery of uterine contents.
PubMed: 38633734
DOI: 10.1002/hsr2.2029 -
Journal of Clinical Medicine Mar 2024Acute coronary syndromes (ACS), encompassing conditions like ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndromes (NSTE-ACS),... (Review)
Review
The Evolving Field of Acute Coronary Syndrome Management: A Critical Appraisal of the 2023 European Society of Cardiology Guidelines for the Management of Acute Coronary Syndrome.
Acute coronary syndromes (ACS), encompassing conditions like ST-elevation myocardial infarction (STEMI) and non-ST-elevation acute coronary syndromes (NSTE-ACS), represent a significant challenge in cardiovascular care due to their complex pathophysiology and substantial impact on morbidity and mortality. The 2023 European Society of Cardiology (ESC) guidelines for ACS management introduce several updates in key areas such as invasive treatment timing in NSTE-ACS, pre-treatment strategies, approaches to multivessel disease, and the use of imaging modalities including computed tomography (CT) coronary angiography, magnetic resonance imaging (MRI), and intracoronary imaging techniques, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS). They also address a modulation of antiplatelet therapy, taking into consideration different patient risk profiles, and introduce new recommendations for low-dose colchicine. These guidelines provide important evidence-based updates in practice, reflecting an evolution in the understanding and management of ACS, yet some potentially missed opportunities for more personalized care and technology adoption are discussed.
PubMed: 38610650
DOI: 10.3390/jcm13071885 -
Clinical Medicine & Research Mar 2024The anti-inflammatory and immunosuppressive properties of steroids allow their use in a wide variety of rheumatological diseases, asthma, inflammatory bowel disease,...
The anti-inflammatory and immunosuppressive properties of steroids allow their use in a wide variety of rheumatological diseases, asthma, inflammatory bowel disease, cancer therapy, and severe viral infections. Though life-saving or organ-saving, long-term clinical use leads to a vast array of complications. Osteoporosis is the most common orthopedic side effect of steroid abuse, while osteonecrosis is a rare occurrence. The risk of osteonecrosis appears to be dose and duration dependent, but several patient factors also play a major role and usually affect the femoral head followed by the knee joint. The long-term effects of steroids must be explained to all patients on therapy, but this risk is missed in individuals who abuse steroids for recreational or performance-enhancing purposes. We describe a male, aged 29 years, who presented with dull aching bilateral knee pain of 2-years' duration after a long-term steroid abuse for weight and muscle mass gain. Radiological and magnetic resonance imaging studies confirmed osteonecrosis of femoral and tibial condyles and secondary degenerative arthritis of the knee joint. Prompt suspicion, early diagnosis, and intervention in osteonecrosis of knee joints, and termination of steroids may reverse the pathology and prevent progression of disease.
Topics: Humans; Male; Knee Joint; Tibia; Femur; Osteonecrosis; Pain; Steroids
PubMed: 38609146
DOI: 10.3121/cmr.2024.1855