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Advanced Materials (Deerfield Beach,... Aug 2023Oral administration is among the most convenient ways with good patient compliance for drug delivery; while it remains a challenge to achieve desirable bioavailability...
Oral administration is among the most convenient ways with good patient compliance for drug delivery; while it remains a challenge to achieve desirable bioavailability of most macromolecules due to the complex gastrointestinal barriers. Here, inspired by the structure and function of rocket, a novel micromotor delivery system is presented with scaled-down rocket-like architecture and effervescent-tablets-derived fuel for efficient oral macromolecule delivery by penetrating intestinal barrier. These rocket-inspired effervescent motors (RIEMs) are composed of sharp needle tips for both loading cargoes and efficient penetrating, and tail wings for loading effervescent powders and avoiding perforation. When exposed to a water environment, the effervescent fuel generates intensive CO bubbles to propel the RIEMs to move at high speed. Thus, the RIEMs with their sharp tip can inject into the surrounding mucosa for effective drug release. Furthermore, benefiting from their tail-wing design, perforation can be effectively avoided during the injection process, ensuring the safety of the RIEMs in gastrointestinal active delivery. Based on these advantages, it is demonstrated that the RIEMs can efficiently move and stab into the intestinal mucosa for insulin delivery, exhibiting efficacy in regulating blood sugar glucose in a diabetic rabbit model. These features indicate that these RIEMs are versatile and valuable for clinical oral delivery of macromolecules.
Topics: Animals; Rabbits; Drug Delivery Systems; Tablets; Administration, Oral; Gastrointestinal Tract; Insulin
PubMed: 37120721
DOI: 10.1002/adma.202210679 -
Journal of Ethnopharmacology Jan 2024Huzhang-Guizhi herb pair (HGHP), composed of Polygonum cuspidatum (Huzhang [HZ] in Chinese, the root of Polygonum cuspidatum Sieb. & Zucc.) and Ramulus Cinnamomi (Guizhi...
Comparative pharmacokinetics and tissue distribution of polydatin, resveratrol, and emodin after oral administration of Huzhang and Huzhang-Guizhi herb-pair extracts to rats.
ETHNOPHARMACOLOGICAL RELEVANCE
Huzhang-Guizhi herb pair (HGHP), composed of Polygonum cuspidatum (Huzhang [HZ] in Chinese, the root of Polygonum cuspidatum Sieb. & Zucc.) and Ramulus Cinnamomi (Guizhi [GZ] in Chinese, the dried twig of Cinnamomum cassia Presl.), is a popular herb pair commonly used to treat arthritis and involved in many Chinese prescriptions. In order to reveal the influence of GZ on HZ on bioavailability, the pharmacokinetic behaviors and tissue distribution variations of the three analytes from HZ were detected between oral administration of HZ and HGHP extracts to rats.
MATERIALS AND METHODS
Male Sprague-Dawley rats were randomly assigned to two groups for pharmacokinetics study and eight groups for tissues distribution research with the equivalent dose of 18 g crude HZ/kg. Assays for analytes from HZ (polydatin, resveratrol, emodin) were developed and validated using high performance liquid chromatography with ultraviolet detection (HPLC-UV).
RESULTS
Part pharmacokinetic parameters including area under the concentration-time curve (AUC), the maximum plasma concentration (C), biological half-life (t), mean residence time (MRT), time to peak concentration (T), clearance rate/bioavailability (CL/F) and volume of distribution/bioavailability (Vd/F) showed significant difference (P < 0.05) after oral administration of HGHP, as compared to those of HZ. The three analytes could be detected in heart, liver, spleen, lung, kidney and brain. Compared with the HZ group, AUC of polydatin in heart, liver and kidney increased significantly (p < 0.05) while that in spleen decreased significantly (p < 0.05); AUC of resveratrol in all detected tissues increased conspicuously (p < 0.05) in the HGHP group; AUC of emodin in heart, liver, spleen, lung, and kidney increased conspicuously (p < 0.05), and decreased obviously (p < 0.05) in brain in the HGHP group.
CONCLUSIONS
GZ could strongly influence the pharmacokinetic parameters and tissue distribution characteristics of polydatin, resveratrol and emodin in rats when administrated with HZ or HGHP extracts. It might provide a reference for further explanation of the compatibility mechanism and the clinical application of HGHP.
Topics: Rats; Male; Animals; Rats, Sprague-Dawley; Emodin; Fallopia japonica; Resveratrol; Tissue Distribution; Plant Extracts; Chromatography, High Pressure Liquid; Administration, Oral; Drugs, Chinese Herbal
PubMed: 37557937
DOI: 10.1016/j.jep.2023.117010 -
Drug Testing and Analysis 2023Capromorelin is a growth hormone secretagogue. Despite promising results to alleviate muscle-wasting in the elderly, it has not advanced further in human development....
Capromorelin is a growth hormone secretagogue. Despite promising results to alleviate muscle-wasting in the elderly, it has not advanced further in human development. Subsequent studies demonstrated capromorelin's ability to increase food intake in animals, leading to approval in the United States and Europe as an appetite stimulant for cats (Elura) and dogs (Entyce). Capromorelin is prohibited in sports due to its ability to stimulate growth hormone production and enhance performance. However, given that its veterinary preparation is formulated as a highly concentrated solution (20 or 30 mg/mL) delivered orally, incidental ingestion or dermal absorption may result in an adverse analytical finding (AAF) by way of direct exposure during oral administration to a pet. An administration study was conducted by either oral or transdermal application of capromorelin solution to mimic the scenario of inadvertent exposure to the drug. Ingestion of 30 μg of capromorelin orally (equivalent to 1 μL of Entyce) resulted in detectable amounts of capromorelin in urine for up to 48 h after administration with a maximum urinary concentration of 7 ng/mL. Importantly, when applied directly to the skin on the hands in larger quantities mimicking a pet administration exposure scenario (30 mg or 1 mL of Entyce), capromorelin was also detected reaching a maximum urinary concentration of 0.7 ng/mL. Athletes and testing authorities should be aware of the risk of an AAF arising due to incidental exposure to veterinary preparations of capromorelin. To our knowledge, before 2022, no positive test for capromorelin had ever been reported.
Topics: Humans; Animals; Dogs; Aged; Piperidines; Pyrazoles; Growth Hormone; Administration, Oral
PubMed: 37688359
DOI: 10.1002/dta.3573 -
Hamostaseologie Jun 2024Venous thromboembolism (VTE) is the third most common cardiovascular disease. For most patients, the standard of treatment has long consisted on low-molecular-weight... (Review)
Review
Venous thromboembolism (VTE) is the third most common cardiovascular disease. For most patients, the standard of treatment has long consisted on low-molecular-weight heparin followed by vitamin K antagonists, but a number of clinical trials and, subsequently, post-marketing studies have shown that direct oral anticoagulants (DOACs) with or without lead-in heparin therapy are effective alternatives with fewer adverse effects. This evidence has led to important changes in the guidelines on the treatment of VTE, including pulmonary embolism (PE), with the DOACs being now recommended as the first therapeutic choice. Additional research has contributed to identifying low-risk PE patients who can benefit from outpatient management or from early discharge from the emergency department with DOAC treatment. There is evidence to support the use of DOACs in intermediate-risk PE patients as well as in high-risk patients receiving thrombolytic treatment. The use of DOACs has also been proven to be safe and effective in special populations of PE patients, such as patients with renal impairment, liver impairment, and cancer.
Topics: Humans; Pulmonary Embolism; Anticoagulants; Administration, Oral; Treatment Outcome; Venous Thromboembolism
PubMed: 38467144
DOI: 10.1055/a-2105-8736 -
Current Allergy and Asthma Reports Apr 2024To review current and future treatment options for IgE-mediated food allergy. (Review)
Review
PURPOSE OF REVIEW
To review current and future treatment options for IgE-mediated food allergy.
RECENT FINDINGS
Recent years have seen major developments in both allergen-specific and allergen-non-specific treatment options, with the first FDA-approved peanut oral immunotherapy (OIT) product becoming available in 2020. In addition to OIT, other immunotherapy modalities, biologics, adjunct therapies, and novel therapeutics are under investigation. Food allergy is a potentially life-threatening condition associated with a significant psychosocial impact. Numerous products and protocols are under investigation, with most studies focusing on OIT. A high rate of adverse events, need for frequent office visits, and cost remain challenges with OIT. Further work is needed to unify outcome measures, develop treatment protocols that minimize adverse events, establish demographic and clinical factors that influence candidate selection, and identify patient priorities.
Topics: Humans; Desensitization, Immunologic; Administration, Oral; Food Hypersensitivity; Allergens; Arachis
PubMed: 38393624
DOI: 10.1007/s11882-024-01133-1 -
Archives of Toxicology Sep 20232,4,7,9-Tetramethyl-5-decyne-4,7-diol (TMDD) is a non-ionic surfactant with a wide range of applications. TMDD is considered a high-production chemical and, due to its...
2,4,7,9-Tetramethyl-5-decyne-4,7-diol (TMDD) is a non-ionic surfactant with a wide range of applications. TMDD is considered a high-production chemical and, due to its low biodegradation rate, possesses a potentially high prevalence in the environment. However, despite its widespread use, toxicokinetic data and data on internal exposure to TMDD in the general population are completely lacking. Hence, we developed a human biomonitoring (HBM) method for TMDD. Our approach included a metabolism study with four subjects, who were administered an oral dose of 75 µg TMDD/kg body weight and a dermal dose of 750 µg/kg body weight. Terminal methyl-hydroxylated TMDD (1-OH-TMDD) was previously identified as the main urinary metabolite in our lab. The results of the oral and dermal applications were used to determine the toxicokinetic parameters of 1-OH-TMDD as a biomarker of exposure. Finally, the method was applied to 50 urine samples from non-occupationally exposed volunteers. Results show that TMDD was rapidly metabolized, with an average t of 1.7 h and a rapid and almost complete (96%) excretion of 1-OH-TMDD until 12 h after oral dosage. Elimination was bi-phasic, with half-lives of 0.75-1.6 h and 3.4-3.6 h for phases 1 and 2, respectively. The dermal application resulted in a delayed urinary excretion of this metabolite with a t of 12 h and complete excretion after about 48 h. The excreted amounts of 1-OH-TMDD represented 18% of the orally administered TMDD dose. The data of the metabolism study demonstrated a fast oral as well as substantial dermal resorption of TMDD. Moreover, the results indicated an effective metabolism of 1-OH-TMDD, which is excreted rapidly and completely via urine. Application of the method to 50 urine samples revealed a quantification rate of 90%, with an average concentration of 0.19 ng/mL (0.97 nmol/g creatinine). With the urinary excretion factor (F) derived from the metabolism study, we estimated an average daily intake of 1.65 µg TMDD from environmental and dietary sources. In conclusion, 1-OH-TMDD in urine is a suitable biomarker of exposure to TMDD and can be applied for biomonitoring of the general population.
Topics: Humans; Kinetics; Surface-Active Agents; Administration, Cutaneous; Pulmonary Surfactants; Biomarkers; Body Weight; Administration, Oral
PubMed: 37392209
DOI: 10.1007/s00204-023-03547-8 -
Drug and Chemical Toxicology Nov 2023Artemisinin-hydroxychloroquine sulfate tablets (AH) are regarded as a relatively inexpensive and novel combination therapy for the treatment of various forms of malaria,...
Artemisinin-hydroxychloroquine sulfate tablets (AH) are regarded as a relatively inexpensive and novel combination therapy for the treatment of various forms of malaria, particularly aminoquinoline drugs-resistant strains of . Our aim was to conduct acute and subacute oral toxicity studies in non-rodents to obtain more nonclinical data on the safety of AH. Acute toxicity evaluation was performed in beagle dogs at single doses of 230, 530, 790, 1180, 2660, and 5000 mg/kg. Beagle dogs at doses of 0, 56, 84, and 126 mg/kg were used to assess subacute toxicity for 14 days. The approximate lethal dose range for acute oral administration of AH in dogs is found to be 790-1180 mg/kg, and toxic symptoms prior to death include gait instability, limb weakness, mental fatigue, tachypnea, and convulsion. Repeated doses of AH in dogs caused vomiting, soft feces, decreased activity, anorexia, and splenic red pulp vacuolation. Of note, AH could reduce body weight gain and prolong the QTc interval of individual dogs. Therefore, the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of oral administration of AH for 14 days in dogs are determined to be 84 mg/kg and 126 mg/kg, respectively.
Topics: Dogs; Animals; Hydroxychloroquine; Artemisinins; No-Observed-Adverse-Effect Level; Administration, Oral; Tablets
PubMed: 36039016
DOI: 10.1080/01480545.2022.2116645 -
Journal of Psychopharmacology (Oxford,... Feb 2024Vortioxetine is efficacious and well tolerated in patients with major depressive disorder (MDD) and is available as an immediate-release tablet and oral drop solution.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vortioxetine is efficacious and well tolerated in patients with major depressive disorder (MDD) and is available as an immediate-release tablet and oral drop solution. The oral drop solution may offer clinical benefits versus a tablet, such as the reduced risk of nausea, personalised dosing and ease of administration.
AIMS
To investigate the bioequivalence of vortioxetine 20 mg/mL oral drop solution versus a 20 mg immediate-release tablet.
METHODS
Healthy adults were randomised 1:1 to receive vortioxetine 20 mg oral drop solution or immediate-release 20 mg tablet after fasting on days 1 and 29 in an open-label, single-centre, single-dose crossover study. The area under the plasma concentration-time curve from 0 to 72 h (AUC) and maximum plasma concentration () were analysed. Bioequivalence was concluded if the 90% CI for the oral drop solution-to-immediate-release tablet ratio for AUC and were contained within a range of 0.80-1.25.
RESULTS
Vortioxetine oral drop solution was bioequivalent to the tablet ( = 26; estimated AUC ratio 1.06 (90% CI: 1.03-1.10); ratio 1.01 (90% CI: 0.97-1.05)). A similar proportion of participants reported adverse events in each study arm but more headache events (7 vs 1) were reported with the oral drop solution versus tablet. The most common adverse event was nausea (16-23% of participants; all mild intensity).
CONCLUSIONS
Vortioxetine oral drop solution is bioequivalent to immediate-release tablets. Oral drop solution provides an alternative to tablets and facilitates clinical benefit through individualised treatment, including gradual dose up-titration, for patients with MDD.
Topics: Adult; Humans; Therapeutic Equivalency; Vortioxetine; Cross-Over Studies; Depressive Disorder, Major; Tablets; Nausea; Administration, Oral
PubMed: 38126222
DOI: 10.1177/02698811231216320 -
International Journal of Pharmaceutics Oct 2023Cannabidiol (CBD) has received great scientific interest due to its numerous therapeutic applications. Degradation in the gastrointestinal (GI) tract, first-pass...
Cannabidiol (CBD) has received great scientific interest due to its numerous therapeutic applications. Degradation in the gastrointestinal (GI) tract, first-pass metabolism, and low water solubility restrain bioavailability of CBD to only 6% in current oral administration. Lipid-based nanocarriers are delivery systems that may enhance accessibility and solubility of hydrophobic payloads, such as CBD. Conventional lecithin-derived liposomes, however, have limitations regarding stability in the GI tract and long-term storage. Ether lipid-based archaeosomes may have the potential to overcome these problems due to chemical and structural uniqueness. In this study, we compared lecithin-derived liposomes with archaeosomes in their applicability as an oral delivery system of CBD. We evaluated drug load, storage stability, stability in a simulated GI tract, and in vitro particle uptake in Caco-2 cells. Loading capacity was 6-fold higher in archaeosomes than conventional liposomes while providing a stable formulation over six months after lyophilization. In a simulated GI tract, CBD recovery in archaeosomes was 57 ± 3% compared to only 34 ± 1% in conventional liposomes and particle uptake in Caco-2 cells was enhanced up to 6-fold. Our results demonstrate that archaeosomes present an interesting solution to tackle current issues of oral CBD formulations due to improved stability and endocytosis.
Topics: Humans; Liposomes; Cannabidiol; Caco-2 Cells; Lecithins; Administration, Oral; Drug Delivery Systems
PubMed: 37739097
DOI: 10.1016/j.ijpharm.2023.123434 -
Journal of Veterinary Internal Medicine 2023Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart...
BACKGROUND
Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart disease.
HYPOTHESIS/OBJECTIVES
To determine if dog characteristics such as age, breed, body condition score, ACVIM stage of heart disease or biochemical laboratory value alter the pharmacokinetics of orally administered pimobendan and its metabolite in a cohort of dogs with naturally occurring MMVD.
ANIMALS
Fifty-seven client-owned dogs with MMVD ACVIM Stage B2, C, or D and administered pimobendan to steady state blood concentrations.
METHODS
Prospective, observational study. Samples were collected using a sparse-sampling protocol at specific intervals after administration of pimobendan. Plasma pimobendan and the active metabolite (O-desmethyl-pimobendan, ODMP) concentrations were determined via high-pressure liquid chromatography and fluorescence detection. Data was analyzed via a population pharmacokinetic approach and nonlinear mixed effects modeling (NLME). Numerous covariates were examined in the NLME model.
RESULTS
The absorption and elimination half-lives (t ) were approximately 1.4 and 1 hour for pimobendan and 1.4 and 1.3 hours for ODMP, respectively. Pharmacokinetic parameters were highly variable, especially the values for pimobendan absorption and elimination rate, and absorption rate of ODMP with coefficients of variation of 147.84%, 64.51% and 64.49%, respectively. No covariate evaluated was a significant source of variability.
CONCLUSIONS AND CLINICAL IMPORTANCE
The pharmacokinetic parameters were highly variable among this group of dogs with MMVD. The variability was not associated with the dog's age, body weight or condition score, stage of heart disease, dose, serum creatinine, or alkaline phosphatase.
Topics: Humans; Dogs; Animals; Mitral Valve; Prospective Studies; Heart Valve Diseases; Heart Diseases; Administration, Oral; Dog Diseases
PubMed: 37776546
DOI: 10.1111/jvim.16891