scholarly journals Unexpected differences in the pharmacokinetics of N-acetyl-DL-leucine enantiomers after oral dosing and their clinical relevance

2019 ◽  
Author(s):  
Grant C. Churchill ◽  
Michael Strupp ◽  
Antony Galione ◽  
Frances M. Platt
Keyword(s):  
Chronic Administration ◽  
The Body ◽  
Maximum Plasma ◽  
Negative Effects ◽  
Chiral Drugs ◽  
Time Curve ◽  
Tissue Samples ◽  
Pharmacologically Active ◽  
Pharmacokinetic Constants ◽  
Noncompartmental Model

AbstractThese results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyl-leucine after administration of the racemate (N-acetyl-DL-leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-leucine). Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (ke and T1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyl-leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the L-enantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of isolated N-acetyl-L-leucine.

scholarly journals Single-Ascending-Dose Pharmacokinetics and Safety of the Novel Broad-Spectrum Antifungal Triazole BAL4815 after Intravenous Infusions (50, 100, and 200 Milligrams) and Oral Administrations (100, 200, and 400 Milligrams) of Its Prodrug, BAL8557, in Healthy Volunteers

2006 ◽  
Vol 50 (1) ◽  
pp. 279-285 ◽  
Author(s):  
Anne Schmitt-Hoffmann ◽  
Brigitte Roos ◽  
Markus Heep ◽  
Michael Schleimer ◽  
Erhard Weidekamm ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Pathogenic Fungi ◽  
Volume Of Distribution ◽  
The Body ◽  
Water Soluble ◽  
Maximum Plasma ◽  
Serious Adverse Events ◽  
Time Curve ◽  
To Receive

ABSTRACT BAL8557 is the water-soluble prodrug of a novel antifungal triazole, BAL4815. BAL4815 is active against a broad spectrum of major opportunistic and pathogenic fungi, including strains that are resistant to other azoles. Cohorts of healthy male subjects received single-ascending oral (p.o.) doses of BAL8557 that were equivalent to 100, 200, or 400 mg of BAL4815 or single-ascending, 1-h constant-rate intravenous (i.v.) infusions of BAL8557 which were equivalent to 50, 100, or 200 mg of BAL4815. In each cohort, six subjects were randomly assigned to receive active drug and two subjects were assigned to receive the placebo. All doses were well tolerated, and no severe or serious adverse events occurred. Maximum plasma concentrations of BAL4815 were observed 1.5 to 3 h after p.o. drug intake or at the end of the 1-h infusion. After both routes of administration, values for maximum drug concentration observed in plasma and area under the concentration-time curve increased slightly more than proportionally to the administered dose. Mean elimination half-lives were particularly long (56 to 77 h after p.o. administration and 76 to 104 h after i.v. administration). The volume of distribution was large (155 to 292 liters after p.o. administration and 304 to 494 liters after i.v. administration) and systemic clearance was low (1.9 to 2.8 liter/h after p.o. administration and 2.8 to 5.0 liter/h after i.v. administration). Urinary recovery of BAL4815 was less than 0.4% of the infused dose. Based on the exposure data, oral bioavailability of BAL4815 is assumed to be very high. The pharmacokinetics of BAL4815 are well suited to maintaining concentrations of BAL4815 for a long period of time in the body and to enabling an effective treatment of systemic mycoses.

Inspector Quadro - the complex of preparation for the treatment of ectoand endoparasitoses in cats and dogs

2018 ◽  
Vol 12 (2) ◽  
pp. 75-84
Author(s):  
M.V. Arisov ◽  
I.P. Belykh ◽  
V.V. Artemov
Keyword(s):  
Body Weight ◽  
Clinical Picture ◽  
High Efficiency ◽  
The Body ◽  
Negative Effects ◽  
Laboratory Methods ◽  
Diagnosis Of Infection

The purpose of the research: the study of the efficacy of the preparations for veterinary use "Inspector Quadro C" and "Inspector Quadro K" against ecto- and endoparasitoses of dogs and cats. Materials and methods. Studies were conducted on spontaneously infected dogs and cats of different sexes, age, weight and breed. The diagnosis of infection with ectoparasites was made based on the clinical picture and laboratory methods of investigation (microscopy of scrapings taken from ectoparasitized skin areas, examination of the coat for fleas, lice, worms, ixodids). Infection with helminths was established by detecting eggs of helminths in faeces of animals by the method of Füleleborn and mature segments of cestodes. Preparations were applied to the animals by drip application on dry undamaged skin in places inaccessible to licking in a dose of 0.1-0.4 ml per 1 kg of body weight. The results were statistically processed. Results and discussion. "Inspector Quadro S" and "Inspector Quadro K" showed 100% efficacy at sarcoptosis in dogs, notoedrosis in cats, otodectosis in dogs and cats, ixodidoses and entomoses. "Inspector Quadro C" showed a high efficiency (92.3%) at demodecosis in dogs. However, single mites were found in one dog. 100% efficacy of "Inspector Quadro C" and "Inspector Quadro K" has been established against intestinal nematodes and cestodes in dogs and cats. Negative effects of drugs on the body of animals have not been revealed.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Cannabis, a complex plant: different compounds and different effects on individuals

2012 ◽  
Vol 2 (6) ◽  
pp. 241-254 ◽  
Author(s):  
Zerrin Atakan
Keyword(s):  
Endocannabinoid System ◽  
The Body ◽  
Vulnerability Factors ◽  
Negative Effects ◽  
Biochemical Basis ◽  
Neurotransmitter System ◽  
Increased Risk ◽  
Opposing Effects ◽  
Available Information ◽  
The Brain

Cannabis is a complex plant, with major compounds such as delta-9-tetrahydrocannabinol and cannabidiol, which have opposing effects. The discovery of its compounds has led to the further discovery of an important neurotransmitter system called the endocannabinoid system. This system is widely distributed in the brain and in the body, and is considered to be responsible for numerous significant functions. There has been a recent and consistent worldwide increase in cannabis potency, with increasing associated health concerns. A number of epidemiological research projects have shown links between dose-related cannabis use and an increased risk of development of an enduring psychotic illness. However, it is also known that not everyone who uses cannabis is affected adversely in the same way. What makes someone more susceptible to its negative effects is not yet known, however there are some emerging vulnerability factors, ranging from certain genes to personality characteristics. In this article we first provide an overview of the biochemical basis of cannabis research by examining the different effects of the two main compounds of the plant and the endocannabinoid system, and then go on to review available information on the possible factors explaining variation of its effects upon different individuals.

scholarly journals Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

2010 ◽  
Vol 55 (1) ◽  
pp. 326-330 ◽  
Author(s):  
José Moltó ◽  
Marta Valle ◽  
Cristina Miranda ◽  
Samandhy Cedeño ◽  
Eugenia Negredo ◽  
...  
Keyword(s):  
High Performance ◽  
Geometric Mean ◽  
Echinacea Purpurea ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Root Extract ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

scholarly journals Antiobesity and Hypolipidemic Activity of Moringa oleifera Leaves against High Fat Diet-Induced Obesity in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Souravh Bais ◽  
Guru Sewak Singh ◽  
Ramica Sharma
Keyword(s):  
Body Weight ◽  
Body Temperature ◽  
Total Cholesterol ◽  
High Fat Diet ◽  
Moringa Oleifera ◽  
Chronic Administration ◽  
The Body ◽  
Atherogenic Index ◽  
High Fat ◽  
Diet Induced Obesity

In the present study, the methanolic extract of Moringa oleifera leaves (MEMOL) was evaluated for antiobesity activity in rats. The antiobesity potential of MEMOL was studied against high fat diet-induced obesity (HFD) in rats. In this study, chronic administration of HFD in rats produced hypercholesterolemia (116.2 ± 0.27 mg/dL), which led to an increase in the body weight (225 gr), total cholesterol, triglycerides (263.0 ± 4.69 mg/dL), and attenuation in the levels of HDL (34.51 ± 2.20 mg/dL) as well as changes in body temperature of animals. Treatment of obese rats with MEMOL for 49 days resulted in a significant (P<0.001) change in body weight, total cholesterol, triglycerides, and LDL level along with a significant (P<0.001) increase in body temperature as compared to the HFD-induced obesity. MEMOL treated rats also showed a significant decrease in the level of liver biomarkers, organ weight, and blood glucose level. Further, rats treated with MEMOL (200 mg and 400 mg/kg) show reduced atherogenic index (1.7 ± 0.6 and 0.87 ± 0.76). The results indicate that the rats treated with Moringa oleifera (MO) have significantly attenuated the body weight without any change in the feed intake and also elicited significant thermogenic effect and to act as hypolipidemic and thermogenic property in obesity related disorders.

EVALUATION OF TOXIOLOGICAL INDICATORS OF MONTHMORRILLONITE CLAY FOR THE PURPOSE OF USING THEM AS ALUMOSILICATE SOBENT AGAINST THE NEGATIVE EFFECT OF MYCOTOXINS ON THE BODY OF ANIMALS AND BIRDS

2021 ◽  
Vol 1 (1) ◽  
pp. 72-78
Keyword(s):  
Experimental Studies ◽  
The Body ◽  
Montmorillonite Clay ◽  
Test Substance ◽  
Negative Effects ◽  
Experimental Animals ◽  
Eyelid Edema ◽  
White Rats ◽  
Mucous Membranes ◽  
Negative Effect

The article presents the results of laboratory studies to assess the toxicological parameters of montmorillonite clay from the Pogadaevskoye deposit in the West Kazakhstan region in order to use them as an aluminosilicate sorbent in the composition of feeds that reduce the negative effects of mycotoxins on the body of animals and birds. The relevance of research is associated with the cultivation of healthy and highly productive animals and poultry in order to ensure the food security of the Republic of Kazakhstan.The studies carried out to assess the toxicological parameters of montmorillonite clay in order to use them as an aluminosilicate sorbent in experimental animals (rabbits and white rats) allowed the following results to be obtained: Visual study of the intensity of erythema when exposed to the test substance on the skin of rabbits showed their absence (0 points). The study of the intensity of edema (an increase in the thickness of the skin clutch of rabbits) when exposed to the test substance on the skin of rabbits showed no reaction (0 points). Studies evaluating the irritating effect of the test substances on the mucous membranes of the eyes of rabbits by symptoms of damage showed the absence of hyperemia (0 points). Weak eyelid edema (1 point), the minimum amount of discharge in the corner of the eye (1 point). The results of studies on the classification assessment of the test substance for the severity of the irritant effect on the eyes of rabbits showed that the average total score of the severity of the irritative effect corresponds to 1 point. A comprehensive analysis of the results obtained on the basis of scientific and experimental studies to assess the toxicological indicators of montmorillonite clay from the Pogadaevskoye deposit in relation to irritating effects on the skin and mucous membranes of experimental animals (rabbits) showed their harmlessness.

DOSE-DEPENDENT CHARACTER OF DISTURBANCE OF HEMATOPOIETIC AND IMMUNE SYSTEMS FUNCTION, PRODUCTION OF SOME HORMONES IN EXPERIMENTAL URANIUM ACETATE DIHYDRATE EXPOSURE

2021 ◽  
Vol 1 (1) ◽  
pp. 14-19
Author(s):  
Е. G. Trapeznikova ◽  
V. В. Popov ◽  
A. S. Radilov ◽  
V. V. Shilov
Keyword(s):  
Hematological Parameters ◽  
Chronic Administration ◽  
Absolute Number ◽  
Uranyl Acetate ◽  
The Body ◽  
Acetate Dihydrate ◽  
Functional Changes ◽  
Cd8 Cells ◽  
Tnf Α ◽  
Dose Dependent

The paper presents the results of an experimental study of the dose-dependent nature of functional changes in the body systems under chronic administration of uranyl acetate dihydrate in doses of 0.5 and 5.0 mg/kg per element for 18 weeks. The study was performed on 45 male outbred rats. It has been shown that uranyl acetate dihydrate in a dose of 0.5 mg/kg had no significant effect on hematological parameters. At the same time, activation of bactericidal activity of neutrophils, a decrease in the immunoregulatory index, and an increase in the blood concentration of tumor necrosis factor (TNF-α) have been revealed. The toxicant administered to rats in a dose of 5 mg/kg led to a decrease in the absolute number of erythrocytes, hemoglobin, hematocrit, platelets, the release of myelocytes into the blood, basophilia, monocytosis, the appearance of leukolysis cells and plasmatization of lymphocytes. On the part of the immune system, an increase in the biocidal capacity of neutrophilic granulocytes, TNF-α production, an increase in the number of CD8+ cells, and a reduction in the CD4+/CD8+ ratio have been found. Uranyl acetate dihydrate had a dose-dependent effect only on the number of cytotoxic T-lymphocytes, T-cells with the CD4+CD8+ phenotype, on the immunoregulatory index, and on the level of TNF-α. Hyperglycemia and glucosuria were also dose-dependent. An increase in glucose in the blood and urine indicated a violation of carbohydrate metabolism and kidney function. There was a decrease in the concentration of thyroxine, testosterone and an increase in the level of insulin. Uranyl acetate dihydrate led to the development of insulin resistance. The level of hormones did not depend on the dose of the toxicant administered to the animals.

The value of functional fermented milk drinks in dietary and preventive nutrition

2021 ◽  
Vol 9 (16) ◽  
pp. 180-191
Author(s):  
Аlla Solomon ◽  
◽  
Iryna Bernyk ◽  
Мariana Bondar ◽  
◽  
...  
Keyword(s):  
Human Body ◽  
Fermented Milk ◽  
The Body ◽  
Biologically Active ◽  
Milk Product ◽  
Negative Effects ◽  
Milk Products ◽  
Adverse Environmental Conditions ◽  
Functional Components ◽  
Fermented Milk Products

State policy in the field of healthy nutrition is a timely and vital, because inadequate nutrition for the physical needs of the body poses a threat to national security today. The article analyzes the state of nutrition of the population of Ukraine in recent years, which is marked by negative trends, both in relation to energy adequacy and in relation to the chemical composition of diets. It is proven that the harm to health is caused by insufficient intake of vitamins, minerals and trace elements, resulting in reduced physical and mental performance, resistance to various diseases, increased negative effects on the body of adverse environmental conditions, harmful production factors, nervous and emotional stress and stress. The purpose of this work is to scientifically substantiate the composition of a fermented milk product enriched with sprouted barley grains and rosehip syrup, which allows improving the structure of the human nutrition through the use of functional ingredients and facilitating the adaptation of the human body to adverse external conditions. Experts associate the positive effect of fermented milk products for the human body with the appearance in them of physiologically active functional components, which are also useful in a physiological form. The value of fermented milk products in functional nutrition is determined primarily by the unique composition of microflora, food and biological value of products. Speaking about the nutritional value of fermented milk products, it is necessary to consider in detail the nutritional substances that make up its composition. In the lifr process of lactic acid bacteria, a complex of biologically active substances (enzymes, lactic and acetic acids, antibiotic substances) is accumulating. Dietary fermented milk products improve metabolism, stimulate the secretion of gastric juice, stimulate the appetite. Improving the health of the human body and ensuring its active life through the use of fermented milk products with functional properties is a new promising direction in medicine and nutrition, as its integral part.

scholarly journals Perceptions of community members towards youth abusing alcohol in the Capricorn District of the Limpopo Province, South Africa

Curationis ◽  
2009 ◽  
Vol 32 (4) ◽  
Author(s):  
T.M. Mothiba ◽  
R.N. Malema
Keyword(s):  
South Africa ◽  
Alcohol Abuse ◽  
Interpersonal Relationships ◽  
Physical Dependence ◽  
Antisocial Behaviour ◽  
The Body ◽  
Limpopo Province ◽  
Negative Effects ◽  
Community Members ◽  
Physical Damage

Alcohol abuse is a problem in South Africa and it has negative effects on the wellbeing of individuals, families, friends, work associates and neighbours. Alcohol produces both psychological and physical dependence. Gillies (1999:112) indicated that alcoholism usually interferes with the ability to socialize, work and may lead to much other destructive behaviour. It was further stated that people who are addicted to alcohol often have a low self-esteem, immaturity, are easily frustrated, and have difficulty in solving personal problems. This study investigated the perceptions of community members towards youth abusing alcohol and identified, among others, anti-social behaviour, poor interpersonal relationships, family disorganization, poor integration with family members and physical damage as the major concerns. An attempt was also made to develop strategies that can be used to overcome the problems of alcohol abuse by youth. Design and Method: A qualitative, exploratory, descriptive and contextual research design was followed in this study for the participants to describe their perceptions regarding the phenomenon in question (Brink, 2006:113). Data were collected through individual unstructured interviews in one village of the Capricorn District of the Limpopo Province. The researchers employed the principles of Guba and Lincoln (1993) cited in De Vos (1998:331) relating to trustworthiness and adhered to the ethical standards as set by the Democratic Nurses Association of South Africa (DENOSA, 1998:2.3.2).Findings: Five themes and seven categories emerged from the data analysis, using Tech’s open coding approach (1990), as outlined in De Vos (1998:343), namely, antisocial behaviour, poor interpersonal behaviour, physical damage, poor progress in life processes and effects of alcohol on the body. To address the problem of alcohol abuse by youth in one village (the study area) of the Capricorn District in the Limpopo Province and other villages the study recommends that educational and recreational facilities and the formation of youth structures should be established.

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