-
Low-dose aspirin therapy for the prevention of preeclampsia: time to reconsider our recommendations?American Journal of Obstetrics and... Oct 2023The American College of Obstetricians and Gynecologists recommends initiation of 81 mg of aspirin daily for women at risk of preeclampsia between 12 and 28 weeks'...
The American College of Obstetricians and Gynecologists recommends initiation of 81 mg of aspirin daily for women at risk of preeclampsia between 12 and 28 weeks' gestation, optimally before 16 weeks, with continuation until delivery. The World Health Organization recommends that 75 mg of aspirin should be initiated before 20 weeks of gestation for women at high risk of preeclampsia. Both the Royal College of Obstetricians and Gynaecologists and the National Institute of Health and Care Excellence quality statement on "Antenatal Assessment of Pre-eclampsia Risk" request that healthcare providers prescribe low-dose aspirin to pregnant women at increased risk of preeclampsia daily from 12 weeks of gestation. The Royal College of Obstetricians and Gynaecologists recommends 150 mg of aspirin daily, and the National Institute of Health and Care Excellence guidelines suggest risk stratification with a dosage of 75 mg for those at moderate risk of preeclampsia and 150 mg for those at high risk of preeclampsia. The International Federation of Gynecology and Obstetrics initiative on preeclampsia recommends 150 mg of aspirin to be initiated at 11 to 14+6 week's gestation and also proposes that 2 tablets of 81 mg is an acceptable alternative. Review of the available evidence suggests that both the dosage and timing of aspirin initiation is key to its effectiveness at reducing the risk of preeclampsia. Doses of >100 mg of aspirin daily initiated before 16 weeks' gestation seem to be most effective at reducing the risk of preeclampsia and thus dosages recommended by most major societies and organizations may not be effective. Randomized control trials examining 81 mg vs 162 mg of aspirin daily for the prevention of preeclampsia are required to assess the safety and efficacy of aspirin dosages available in the United States.
Topics: Female; Pregnancy; Humans; Pre-Eclampsia; Platelet Aggregation Inhibitors; Aspirin; Pregnancy Trimester, First; Gestational Age
PubMed: 37120049
DOI: 10.1016/j.ajog.2023.04.031 -
American Journal of Nephrology 2021The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD...
INTRODUCTION
The nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated clinical benefits in CKD patients with type 2 diabetes. Clinical data analyzing the potential value of a combination therapy are currently limited. We therefore investigated cardiorenal protection of respective mono- and combination therapy in a preclinical model of hypertension-induced end-organ damage.
METHODS
Cardiovascular (CV) morbidity and mortality were studied in hypertensive, N(ω)-nitro-L-arginine methyl ester-treated, renin-transgenic (mRen2)27 rats. Rats (10- to 11-week-old females, n = 13-17/group) were treated once daily orally for up to 7 weeks with placebo, finerenone (1 and 3 mg/kg), empagliflozin (3 and 10 mg/kg), or a combination of the respective low doses. Key outcome parameters included mortality, proteinuria, plasma creatinine and uric acid, blood pressure, and cardiac and renal histology.
RESULTS
Placebo-treated rats demonstrated a 50% survival rate over the course of 7 weeks. Drug treatment resulted in variable degrees of survival benefit, most prominently in the low-dose combination group with a survival benefit of 93%. Monotherapies of finerenone or empagliflozin dose-dependently reduced proteinuria, while low-dose combination revealed an early, sustained, and over-additive reduction in proteinuria. Empagliflozin induced a strong and dose-dependent increase in urinary glucose excretion which was not influenced by finerenone coadministration in the combination arm. Low-dose combination but not respective low-dose monotherapies significantly reduced plasma creatinine and plasma uric acid after 6 weeks. Treatment with finerenone and the low-dose combination significantly decreased systolic blood pressure after 5 weeks. There was a dose-dependent protection from cardiac and kidney fibrosis and vasculopathy with both agents, while low-dose combination therapy was more efficient than the respective monotherapy dosages on most cardiorenal histology parameters.
DISCUSSION/CONCLUSIONS
Nonsteroidal MR antagonism by finerenone and SGLT2 inhibition by empagliflozin confer CV protection in preclinical hypertension-induced cardiorenal disease. Combination of these 2 independent modes of action at low dosages revealed efficacious reduction in important functional parameters such as proteinuria and blood pressure, plasma markers including creatinine and uric acid, cardiac and renal lesions as determined by histopathology, and mortality indicating a strong potential for combined clinical use in cardiorenal patient populations.
Topics: Animals; Benzhydryl Compounds; Disease Models, Animal; Drug Combinations; Female; Glucosides; Heart Diseases; Hypertension; Kidney Diseases; Naphthyridines; Rats; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 34111864
DOI: 10.1159/000516213 -
Chest Feb 2023Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD.
RESEARCH QUESTION
Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement?
STUDY DESIGN AND METHODS
Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event).
RESULTS
At 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003) INTERPRETATION: Higher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD.
TRIAL REGISTRY
ClinicalTrials.gov; No.: NCT02630316; URL: www.
CLINICALTRIALS
gov.
Topics: Humans; Hypertension, Pulmonary; Antihypertensive Agents; Treatment Outcome; Epoprostenol; Lung Diseases, Interstitial; Double-Blind Method
PubMed: 36115497
DOI: 10.1016/j.chest.2022.09.007 -
Therapeutic Drug Monitoring Apr 2023Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is...
Nirmatrelvir/ritonavir (Paxlovid) consists of a peptidomimetic inhibitor (nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Coadministration of nirmatrelvir/ritonavir with immunosuppressive drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. Although a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here, we provide some general recommendations for therapeutic drug monitoring of ISDs and dosing recommendations when coadministered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day 1, whereas cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.
Topics: Humans; Ritonavir; Drug Monitoring; Cytochrome P-450 CYP3A; COVID-19; COVID-19 Drug Treatment; SARS-CoV-2; Immunosuppressive Agents
PubMed: 35944126
DOI: 10.1097/FTD.0000000000001014 -
Journal of Investigational Allergology... Jul 2021According to current guidelines, oral antihistamines are the first-line treatment for chronic spontaneous urticaria (CSU). Up-dosing antihistamines to 4-fold the...
BACKGROUND AND OBJECTIVES
According to current guidelines, oral antihistamines are the first-line treatment for chronic spontaneous urticaria (CSU). Up-dosing antihistamines to 4-fold the licensed dose is recommended if control is not achieved. Such indications are based mainly on expert opinion. Objectives: To critically review and analyze clinical evidence on the efficacy and safety of higher-than-licensed dosage of second-generation oral antihistamines in the treatment of CSU.
MATERIAL AND METHODS
A systematic literature review was performed following a sensitive search strategy. All articles published in PubMed, EMBASE, and the Cochrane Library between 1961 and October 2018 were examined. Publications with CSU patients prescribed secondgeneration antihistamines in monotherapy compared with placebo, licensed dosages, and/or higher dosages were included. Articles were evaluated by peer reviewers. Quality was evaluated using the Jadad and Oxford scores.
RESULTS
We identified 337 articles, of which 14 were included in the final evaluation (fexofenadine, 6; cetirizine, 2; levocetirizine and desloratadine, 1; levocetirizine, 1; rupatadine, 2; ebastine, 1; and bilastine, 1). Only 5 studies were placebo-controlled. The number of patients included ranged from 20 to 439. The observation lapse was ≤16 weeks. High fexofenadine doses produced a significant dosedependent response and controlled urticaria in most patients. Cetirizine, levocetirizine, rupatadine, and bilastine were more effective in up-dosing. The most frequent adverse events were headache and drowsiness.
CONCLUSION
The low quality and heterogeneity of the articles reviewed made it impossible to reach robust conclusions and reveal the need for large-scale randomized clinical trials.
Topics: Administration, Oral; Animals; Anti-Allergic Agents; Chronic Urticaria; Clinical Trials as Topic; Drug Dosage Calculations; Drug-Related Side Effects and Adverse Reactions; Histamine H1 Antagonists, Non-Sedating; Humans; Treatment Outcome
PubMed: 33030434
DOI: 10.18176/jiaci.0649 -
FP Essentials Apr 2024Micronutrients are nutrients the body needs in small quantities, such as vitamins and minerals. Micronutrient deficiencies can occur when an individual is restricting... (Review)
Review
Micronutrients are nutrients the body needs in small quantities, such as vitamins and minerals. Micronutrient deficiencies can occur when an individual is restricting calorie intake for weight loss or management, not consuming an adequate amount of food to meet energy requirements due to poor appetite or illness, eliminating one or more food groups from the diet on a regular basis, or consuming a diet low in micronutrient-rich foods despite adequate or excessive energy intake. Patient groups at risk include older adults, pregnant patients, patients with alcohol use disorder, patients with vegetarian or vegan diets, and patients with increased requirements secondary to medical conditions or long-term drug use that alters nutrient absorption, metabolism, or excretion. The micronutrients that most commonly require supplementation are vitamin D, iron, vitamin A, zinc, folate, and iodine. Results of large-scale randomized trials have shown no overall benefit of multivitamins for the majority of patients. However, a daily multivitamin may be beneficial, particularly for patients who do not consistently consume a well-balanced diet. Although dietary supplements can be helpful in correcting deficiencies, higher than recommended doses can cause adverse effects. Patients should be advised to take recommended dosages of supplements and consult their physician if they notice any adverse effects. Physicians should advise patients to consult drug labels and/or pharmacists about potential supplement interactions with drugs or other supplements.
Topics: Humans; Micronutrients; Dietary Supplements; Vitamins; Female; Nutritional Requirements; Pregnancy; Zinc
PubMed: 38648170
DOI: No ID Found -
Expert Review of Anti-infective Therapy Jul 2019: Ceftriaxone has been recommended as a first-line treatment for various infections; however, the doses for pneumonia have not been a consensus in randomized clinical... (Comparative Study)
Comparative Study Meta-Analysis
: Ceftriaxone has been recommended as a first-line treatment for various infections; however, the doses for pneumonia have not been a consensus in randomized clinical trials. To compare ceftriaxone 1 g daily efficacy to other ceftriaxone dosing regimens in community-acquired pneumonia. : We performed a systematic review and meta-analysis on PubMed, Web of Science, Scopus, and LILACS. Randomized controlled trials of ceftriaxone in community-acquired pneumonia were included. Outcomes included clinical cure in modified intention-to-treatment, clinically and microbiologically evaluable patients. : Ceftriaxone dosages of 1 g daily are as safe and effective as other antibiotic regimens for community-acquired pneumonia. Twenty-four articles fulfilled the inclusion criteria. Twelve studies evaluated ceftriaxone regimens at a dosage of 2 g daily and 12 studies evaluated ceftriaxone at a dosage of 1 g daily. The odds-ratio of clinical cure in the modified intention-to-treatment patients administered either ceftriaxone (4666 patients) or a comparator (4411 patients) was 0.98 (95% CI [0.82-1.17]). Comparator regimens showed similar efficacy to ceftriaxone regimens of 1 g daily, with an odds ratio of 1.03 (95% CI [0.88-1.20]). Dosages higher than ceftriaxone 1 g daily did not result in improved clinical outcomes for community-acquired pneumonia patients (OR 1.02, 95% CI [0.91-1.14]).
Topics: Anti-Bacterial Agents; Ceftriaxone; Community-Acquired Infections; Dose-Response Relationship, Drug; Humans; Pneumonia; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31179786
DOI: 10.1080/14787210.2019.1627872 -
Current Protein & Peptide Science 2020Nano-inspired technologies offer unique opportunities to treat numerous diseases by using therapeutic peptides. Therapeutic peptides have attractive pharmacological... (Review)
Review
Nano-inspired technologies offer unique opportunities to treat numerous diseases by using therapeutic peptides. Therapeutic peptides have attractive pharmacological profiles and can be manufactured at relatively low costs. The major advantages of using a nanodelivery approach comprises significantly lower required dosages compared to systemic delivery, and thus reduced toxicity and immunogenicity. The combination of therapeutic peptides with delivery peptides and nanoparticles or small molecule drugs offers systemic treatment approaches, instead of aiming for single biological targets or pathways. This review article discusses exemplary state-of-the-art nanosized delivery systems for therapeutic peptides and antibodies, as well as their biochemical and biophysical foundations and emphasizes still remaining challenges. The competition between using different nanoplatforms, such as liposome-, hydrogel-, polymer-, silica nanosphere-, or nanosponge-based delivery systems is still "on" and no clear frontrunner has emerged to date.
Topics: Animals; Antibodies; Biological Transport; Cell-Penetrating Peptides; Diffusion; Drug Delivery Systems; Humans; Hydrogels; Liposomes; Nanoparticles; Neoplasms; Peptides, Cyclic; Phagocytosis; Protein Stability; Proteolysis
PubMed: 31793426
DOI: 10.2174/1389203720666191202112429 -
Obstetrics and Gynecology Clinics of... Mar 2023Epilepsy affects up to 15 million of people assigned female at birth of childbearing age globally. Up to 65% of these people with epilepsy and gestational capacity have... (Review)
Review
Epilepsy affects up to 15 million of people assigned female at birth of childbearing age globally. Up to 65% of these people with epilepsy and gestational capacity have an unplanned pregnancy. Seizure control during pregnancy is important for both the childbearer's and fetus' safety. There are multiple antiseizure medications (ASMs) that can be used to control epilepsy; however, each medication has its own teratogenic risk profile, which must be considered. The majority of these ASMs will require frequent plasma concentration monitoring during pregnancy with corresponding dosage adjustments. Dosages can be reduced back to prepregnancy levels within 3 weeks postpartum. Breastfeeding on ASMs is recommended.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Breast Feeding; Fetus; Parturition; Postpartum Period; Pregnancy, Unplanned; Anticonvulsants
PubMed: 36822708
DOI: 10.1016/j.ogc.2022.10.014