Safety of oral administration of high doses of ivermectin by means of biocompatible polyelectrolytes formulation.
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SUBMITTER: Madrid RRM
PROVIDER: S-EPMC7775035 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundStrongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined.MethodsA prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up.ResultsNinety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2-76) weeks in albendazole group, 39 (2-74) weeks in single dose ivermectin group, and 26 (2-74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin, and double doses of oral ivermectin respectively (P = 0.006) in modified intention to treat analysis. No serious adverse event associated with treatment was found in any of the groups.Conclusion/significanceThis study confirms that both a single, and a double dose of oral ivermectin taken two weeks apart, is more effective than a 7-day course of high dose albendazole for patients with chronic infection due to S. stercoralis. Double dose of ivermectin, taken two weeks apart, might be more effective than a single dose in patients with concomitant illness.Trial registrationClinicalTrials.gov NCT00765024.
| S-EPMC3091835 | biostudies-literature
Project description:Antioxidants are molecules that delay or inhibit the oxidation of other molecules. Its use significantly increased in recent years in the diet of people. Natural antioxidants are replacing the use of synthetic antioxidant ingredients due to their safety, nutritional, and therapeutic values. Hydrolyzed collagen (HC) is a popular ingredient considered to be an antioxidant. This low molecular weight protein has been widely utilized due to its excellent biocompatibility, easy biodegradability, and weak antigenicity. It is a safe cosmetic biomaterial with good moisturizing properties on the skin. The antioxidant properties of HC are conditioned to the size of the molecule: the lower the molecular weight of peptides, the greater the ability to donate an electron or hydrogen to stabilize radicals. The antioxidant capacity of HC is mostly due to the presence of hydrophobic amino acids in the peptide. The exact mechanism of peptides acting as antioxidants is not clearly known but some aromatic amino acids and histidine are reported to play an important role in the antioxidant activity. Oral ingestion of HC increases the levels of collagen-derived peptides in the blood torrent and improves the skin properties such as elasticity, skin moisture, and transepidermal water loss. Additionally, daily intakes of HC protect the skin against UV melasma, enhances the fibroblast production and extracellular matrix of the skin. HC has been identified as a safe cosmetic ingredient for topical formulations with good moisturizing properties at the stratum corneum layer of the skin. It reduces the effects of skin aging (dryness, laxity, and wrinkles). The use of HC as a principal ingredient in safe formulations for skin protection was reviewed and compared when it is used by topical and/or oral administration.
| S-EPMC7070905 | biostudies-literature
Project description:Purpose:Lidocaine (LID) is a local anesthetic that is administered either by injection and/or a topical/transdermal route. However, there is a current need to develop efficacious methods for the oral delivery of LID with optimized bioavailability. Methods:We developed oral LID biodegradable microspheres that were loaded with alginate-chitosan with different mass ratios, and characterized these microspheres in vitro. We also developed, and utilized, a simple and sensitive HPLC-tandem mass spectrometry (LC-MS-MS) method for assaying LID microspheres. Results:The mean particle size (MPS) of the LID microspheres ranged from 340.7 to 528.3 nm. As the concentration of alginate was reduced, there was a significant reduction in MPS. However, there was no significant change in drug entrapment efficiency (DEE), or drug yield, when the alginate concentration was either increased or decreased. DSC measurements demonstrated the successful loading of LID to the new formulations. After a slow initial release, less than 10% of the LID was released in vitro within 4 h at pH 1.2. In order to evaluate nephrotoxicity, we carried out MTT assays of LID in two types of cell line (LLC-PK1 and MDCK). LID significantly suppressed the cell toxicity of both cell lines at the concentrations tested (100, 200, and 400ng/µL). Conclusion:Experiments involving the oral delivery of LID formulations showed a significant reduction in particle size and an improvement in dissolution rate. The formulations of LID developed exhibit significantly less toxicity than LID alone.
| S-EPMC7008179 | biostudies-literature
Project description:BackgroundAbout 3·7 billion doses of ivermectin have been distributed in mass drug administration (MDA) campaigns globally over the past 30 years. At 10-100 times higher than current human doses, ivermectin is a known teratogen in mammals. During these campaigns with recommended doses, pregnant women might be inadvertently exposed. We therefore aimed to evaluate the existing evidence for serious and non-serious adverse events after ivermectin exposure in pregnant women.MethodsFor this systematic review and meta-analysis, we searched relevant databases and trial registry platforms on July 15, 2018, for randomised controlled trials (RCTs) and observational studies that reported adverse events in pregnant women. We did not use language or date restrictions. Outcomes of interest were spontaneous abortions, stillbirths, congenital anomalies, and neonatal death (serious adverse events), as well as maternal morbidity, preterm births, and low birthweight (adverse events). The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias Tool for RCTs. We did the meta-analysis of observational studies and RCTs separately. The quality of evidence was assessed using the GRADE approach. The study protocol is registered with PROSPERO, protocol CRD42016046914.FindingsWe identified 147 records, of which only five observational studies and one RCT were included for quantitative analysis; these studies were published between 1990 and 2008, and were done in six African countries. 893 women with 899 pregancy outcomes were included, of whom 496 pregnant women (500 pregnancy outcomes) received ivermectin inadvertently during MDA campaigns in the observational studies and 397 pregnant women (399 pregnancy outcomes) purposely received ivermectin as part of the open-label RCT. No study reported neonatal deaths, maternal morbidity, preterm births, or low birthweight. It is unclear whether exposure to ivermectin during pregnancy increases the risk of spontaneous abortions and stillbirths (odds ratio [OR] 1·15 [95% CI 0·75-1·78] with very low certainty of evidence for the four observational studies and 0·62 [0·18-2·14] with very low certainty of evidence for the RCT) or congenital anomalies (OR 1·69 [95% CI 0·83-3·41] with very low certainty of evidence for the five observational studies and 1·10 [0·07-17·65] with very low certainty of evidence for the RCT).InterpretationThere is insufficient evidence to conclude on the safety profile of ivermectin during pregnancy. Treatment campaigns should focus additional efforts on preventing inadvertent treatment of pregnant women.FundingUnitaid.
| S-EPMC7613514 | biostudies-literature
Project description:Ivermectin (IVM) is an anthelmintic compound commonly used off-label in mules due to its broad-spectrum of activity. Despite the general use of IVM in mules with the same dose and route of administration licensed for horses, significant pharmacokinetic differences might exist between horses and mules, as already observed for donkeys. The aim of the present study was to evaluate the pharmacokinetic profile and anthelmintic efficacy of an oral paste of IVM in mules naturally infected with cyathostomins. Fifteen adult mules with fecal egg counts (FEC) ≥200 eggs per gram (EPG), with exclusive presence of cyathostomins, were included in the study. All mules were orally treated with IVM according to the manufacturer's recommended horse dosage (200 µg/kg body weight). FECs were performed before (day-10 and day-3) and after treatment at days 14 and 28 by using a modified McMaster method. The FEC reduction (FECR%) was also calculated. Blood samples were collected from five animals at various times between 0.5 h up to 30 days post treatment to determine pharmacokinetic parameters. The maximum IVM serum concentration (Cmax) was 42.31 ± 10.20 ng/mL and was achieved at 16.80 ± 9.96 hours post-treatment (Tmax), area under the curve (AUC) was 135.56 ± 43.71 ng × day/mL. FECR% remained high (>95%) until the 28th day.
| S-EPMC7341313 | biostudies-literature
Project description:BackgroundNonsteroidal anti-inflammatory drugs are administered in horses for several systemic diseases. Selective cyclooxygenase-2 inhibitors are preferred because of lower risk of adverse effects. Several meloxicam formulations have been tested in horses, but a recently marketed granule oral formulation has not been studied.ObjectiveTo characterize the pharmacokinetics of a novel granule meloxicam formulation in fasted and fed horses, and to compare pharmacokinetic features with oral suspension and tablets.AnimalsSeven healthy adult horses.MethodsMeloxicam was administered at 0.6 mg/kg in fasted or fed horses. Blood samples were collected for pharmacokinetic analysis, and vital signs, hematology, and biochemistry variables were monitored for 72 hours.ResultsNo adverse effects were detected. Volume of distribution and clearance after intravenous administration of meloxicam were 0.36 L/kg and 29.12 mL/h/kg, respectively, with a 12.39 hours of terminal half-life. Protein binding was of 97%. Bioavailability was high for every oral formulation, ranging 70%-110%, without feed effect. Because of a slower absorption, meloxicam after administration of granules had a longer half-life (24 and 34 hours, fasted and fed, respectively) and mean residence time (31 and 47 hours), than suspension and tablets (ranging 10-13 and 13-15 hours, respectively). In addition, the time above therapeutic concentration was higher for the granule formulation than other formulations.Conclusions and clinical importanceGranule formulation has different PK parameters compared to other oral formulations, which could enable this formulation to be used for different dosage regimens in order to reach a desired clinical effect or decrease the risk of adverse effects.
| S-EPMC6430890 | biostudies-literature
Project description:The aim of this study was to assess and compare the pharmacokinetics (PK) and safety of Enasidenib in healthy adult male Japanese subjects to healthy adult male Caucasian subjects. This was a phase 1, single dose study to evaluate the PK and safety of Enasidenib in healthy adult male Japanese subjects relative to healthy adult male Caucasian subjects. A total of 62 subjects (31 Japanese and 31 Caucasian) were enrolled into three dose cohorts (single doses of 50 mg, 100 mg, or 300 mg Enasidenib). Blood samples for PK assessment were collected up to 672 hours postdose. Safety was evaluated throughout the study. In the present study, we found that PK exposures of Enasidenib and its metabolite AGI-16903 for Caucasian and Japanese subjects were comparable at the 50, 100, and 300 mg dose levels, demonstrated by that the 90% confidence intervals (CIs) of geometric mean ratios for AUCs and C max between these two populations generally contained 100% from all three treatment cohorts. In conclusion, PK exposures of Enasidenib and its metabolite AGI-16903 for Caucasians and Japanese subjects were comparable and Enasidenib was safe and well tolerated with no apparent differences between Japanese and Caucasian subjects when administered as single oral doses of 50 mg, 100 mg, and 300 mg.
| S-EPMC6199364 | biostudies-other
Project description:Background:Ivermectin (IVM) has been widely used in the aquaculture industry since its efficacy against parasites. However, the degradation of IVM was very slow in aquatic environments and the environmental fate of IVM in a complete aquatic system was still not clear. Therefore, comparable studies in a complete aquatic system were merited and helped to elucidate the environmental fate and effects of IVM. Methods:An aquatic micro-ecological system containing an aquatic environment (water and sediment) and aquatic organisms (invertebrates, aquatic plants and fish) was built to simulate the natural rearing conditions. A single dose of 0.3 mg kg-1 body weight of IVM was given to the fish by oral gavage. Water, sediment, the roots and leaves of the aquatic plants, the soft tissue of the invertebrates and the visceral mass and muscle of fish samples were collected at 0.5 hours, 1 day, 7 days, 15 days, 30 days, 45 days, 60 days and 70 days after the treatment. IVM concentration in each sample was determined using ELISA method. Results:IVM was quickly and widely distributed into the whole aquatic system in one day, and then was highly accumulated in organisms resulting in long-term residues. IVM was exchanged multiple times between the different media, which caused continuous fluctuations in the concentration of IVM in the water and sediment. It was worth noting that there was a second peak value of IVM in the fish and invertebrates after 30 days. The environmental fate of the IVM in the aquatic micro-ecological system showed that the drug was transferred from the fish to aquatic plants in the first seven days, and then gathered in the water and sediment, finally accumulating in the invertebrates. Our results indicated that an effective aquatic micro-ecological system was successfully established, and it could be applied to the study the environmental fate of IVM, which will aid the scientific use of this anti-parasitic agent during aquaculture.
| S-EPMC6790101 | biostudies-literature
Project description:ObjectiveTo estimate the level of dispensing of oral corticosteroids (OCS) for managing asthma in Australia, with a particular focus on the cumulative dispensing of doses associated with long term toxicity (≥ 1000 mg prednisolone-equivalent).DesignRetrospective cohort study; analysis of 10% random sample of Pharmaceutical Benefits Scheme (PBS) dispensing data.Participants, settingPeople aged 12 years or more treated for asthma during 2014-2018, according to dispensing of controller inhaled corticosteroids (ICS).Main outcome measuresNumber of people dispensed OCS for managing asthma during 2014-2018; proportion who were cumulatively dispensed at least 1000 mg prednisolone-equivalent. The secondary outcome was the number of people dispensed at least 1000 mg prednisolone-equivalent during 2018, stratified by inhaler controller dose and use.Results124 011 people had been dispensed at least two prescriptions of ICS during 2014-2018 and met the study definition for asthma, of whom 64 112 (51.7%) had also been dispensed OCS, including 34 580 (27.9% of the asthma group) cumulatively dispensed 1000 mg prednisolone-equivalent or more. Of 138 073 people dispensed OCS at this level, 68 077 (49%) were patients with airway diseases. Dispensing of diabetes and osteoporosis medications was more common for people cumulatively dispensed 1000 mg prednisolone-equivalent or more. During 2018, 4633 people with asthma using high dose ICS controllers were dispensed 1000 mg prednisolone-equivalent or more, for 2316 of whom (50%) controller use was inadequate.ConclusionsCumulative exposure to OCS in Australia reaches levels associated with toxicity in one-quarter of patients with asthma using ICS. Cumulative dispensing of potentially toxic OCS amounts often accompanies inadequate inhaler controller dispensing. Better approaches are needed to improve adherence to controller therapy, improve outcomes for people with asthma, and to minimise the use and toxicity of OCS.
| S-EPMC7589219 | biostudies-literature
Project description:Nonporous silica nanoparticles (SiNPs) have potential as promising carriers for ophthalmic drugs. However, the in vivo safety of ocular topical SiNPs remains unclear. This study investigated the in vivo safety of oral and ocular topical applications of 100 nm-sized SiNPs in Sprague-Dawley rats. The rats were divided into the following four groups: low-dose oral administration (total 100 mg/kg of SiNPs mixed with food for one week), high-dose oral administration (total 1000 mg/kg of SiNPs mixed with food for one week), ocular topical administration (10 mg/ml concentration, one drop, applied to the right eyes four times a day for one month), or a negative control (no SiNP treatment). The rats were observed for 12 weeks to investigate any signs of general or ocular toxicity. During the observation period, no differences were observed in the body weights, food and water intakes, behaviors and abnormal symptoms of the four groups. No animal deaths occurred. After 12 weeks, hematologic, blood biochemical parameters and ophthalmic examinations revealed no abnormal findings in any of the animals. The lack of toxicity of the SiNPs was further verified in autopsy findings of brain, liver, lung, spleen, heart, kidneys, intestine, eyeballs, and ovaries or testes.
| S-EPMC5557988 | biostudies-literature