Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 ...enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min−1, kinact/Ki = 0.03 min−1 µM−1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food–drug interactions have to be assessed clinically.
Addiction is a complex psychosocial problem that has significant psychosocial effects on family members. The aim of this study is to gain insight into the burden and psychological distress suffered ...by caregivers of drug abusers. Ninety-nine caregivers of hard drug addicts participated in this study. The test group consisted of 50 participants and the control group had 49 participants. The participants filled out the General Demographic Questionnaire; Caregiving and the Experience of Subjective and Objective Burden; SCL-90-R; and WHOQOL-BREF. Caregivers of addicts who were preparing to join the community exhibited a significantly higher objective burden, subjective burden, subjective stress burden and greater psychological distress in comparison to caregivers of addicts in the community, and their quality of life was poorer (p < 0.001). The following showed to be risk factors for psychological distress: families with a greater number of children, marital, employment and economic status and duration of addiction. The protective factors were better quality of life, long-term marriage and higher education level of caregivers. Caring for addicts who are living with their families is a significant responsibility and burden for caregivers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The biological effects of drug vehicles are often overlooked, often leading to artifacts in acetaminophen-induced liver injury assessment. Therefore, we decided to investigate the effect of ...dimethylsulfoxide, dimethylformamide, propylene glycol, ethanol, and Tween 20 on acetaminophen-induced liver injury. C57BL/6 male mice received a particular drug vehicle (0.6 or 0.2 mL/kg, i.p.) 30 min before acetaminophen administration (300 mg/kg, i.p.). Control mice received vehicle alone. Liver injury was assessed by measuring the concentration of alanine aminotransferase in plasma and observing histopathological changes. The level of reduced glutathione (GSH) was assessed by measuring total nonprotein hepatic sulfhydrils. Dimethylsulfoxide and dimethylformamide (at both doses) almost completely abolished acetaminophen toxicity. The higher dose of propylene glycol (0.6 mL/kg) was markedly protective, but the lower dose (0.2 mL/kg) was only slightly protective. These solvents also reduced acetaminophen-induced GSH depletion. Dimethylformamide was protective when given 2 h before or 1 h after acetaminophen administration, but was ineffective if given 2.5 h after acetaminophen. Ethanol at the higher dose (0.6 mL/kg) was partially protective, whereas ethanol at the lower dose (0.2 mL/kg) as well as Tween 20 at any dose had no influence. None of the vehicles (0.6 mL/kg) was hepatotoxic per se, and none of them was protective in a model of liver injury caused by
d
-galactosamine and lipopolysaccharide.
Celotno besedilo
Dostopno za:
DOBA, FSPLJ, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Schizophrenia is a multifactorial neurodevelopmental disorder associated with cognitive dysfunction and changes in primary sensory processing. This article aims to explore the current insights into ...the relationship between schizophrenia and different visual disturbances.
To provide a literature review of visual impairments in schizophrenia, we performed a PubMed/MEDLINE and Scopus search to identify all articles in English on the topic up to the end of 2018.
Multiple retinal functional and structural abnormalities are found in patients with schizophrenia. Wider retinal venules suggest chronically insufficient brain supply of oxygen and this could contribute to the occurrence of psychotic symptoms. Optical coherence tomography studies showed that retinal nerve fiber layer, macular thickness, and macular volume were significantly lowered in the chronic phase of schizophrenia. Results from electroretinogram recordings have demonstrated different declinations such as abnormalities of a - wave activity in the photoreceptors or b - wave activity in the bipolar and Muller cells. Abnormalities in eye movements, such as a notable decrease in saccades and smooth pursuit eye movements, are one of the most reliable and reproducible impairments associated with schizophrenia. Disrupted visual processing of the magnocellular pathway may result in a decrease of contrast sensitivity, sensory processing, orientation discrimination, visual integration, trajectory and spatial localization, backward masking and motion tracking. Visual perceptual abnormalities occur in more than 60% of schizophrenic patients and these are visual hallucinations, perceptual distortion of colors, shapes and light intensity, decrease in contour integration and surround suppression. Other, frequently present eye disorders include impaired visual acuity, strabismus and nystagmus.
Visual impairments are one of the most important features of schizophrenia, which could help in defining the disease state and assigning appropriate treatment.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare condition. Here, we present a case of a male patient with a very unique combination of symptoms ...that started at the age of 12. Transient symptoms manifested after 4 days of high fever and included lethargy, a loss of appetite, and an inability to recognize faces. After that, the patient was symptom-free for 4 years before he was hospitalized again with a working diagnosis of acute disseminated encephalomyelitis. The ophthalmic symptoms at this stage were photophobia and discrete horizontal nystagmus. One year later, the patient had another seizure and during hospitalization, predominantly displayed cerebral symptoms such as dystaxia, dysmetria, generalized muscle hypotrophy, and absent myotonic reflexes. Like before, an ophthalmic examination demonstrated a best-corrected visual acuity of 1.0 and a normal anterior segment. A fundus examination revealed a slightly rarefied retina, along with areas of perifoveal and parapapillary atrophy, in addition to increased vascular tortuosity. Optical coherence tomography scans of the macula and the optic disc depicted a mild thinning of the retinal layers. Visual field testing showed an isopter contraction with a predominant loss of the temporal visual field in both eyes. A genetic serum analysis was positive for mitochondrial mutation m.3243A>G, and a diagnosis of MELAS was confirmed. The treatment included anticonvulsive drugs and dietary precautions. Patients with MELAS syndrome can manifest a wide range of visual disturbances, meaning that a detailed ophthalmic examination is required.
This study aimed to investigate the influence of silicone oil on the retinal nerve fiber layer (RNFL) thickness in patients with primary rhegmatogenous retinal detachment who underwent vitreoretinal ...surgery. The study included 47 patients (eyes), who underwent a pars plana vitrectomy with the silicone oil tamponade. The control group included unoperated eye of all participants. Spectral-domain optical coherence tomography (SD-OCT) was used for the measurements of peripapilar and macular RNFL thickness. The average peripapillary RNFL thickness was significantly higher in the silicone oil filled eyes during endotamponade and after its removal. The eyes with elevated IOP had less thickening of the RNFL in comparison to the eyes with normal IOP. Central macular thickness and macular volume were decreased in the silicone oil filled eyes in comparison to the control eyes. In conclusion, silicone oil caused peripapilar RNFL thickening in the vitrectomized eyes during endotamponade and after silicone oil removal.
Cytochrome P450 3A4 is the most significant enzyme in metabolism of medications. Flavonoids are common secondary plant metabolites found in fruits and vegetables. Some flavonoids can interact with ...other drugs by inhibiting cytochrome P450 enzymes. Thus, the objective of this study was to determine inhibition kinetics of cytochrome P450 3A4 by flavonoids: acacetin, apigenin, chrysin and pinocembrin. For this purpose, testosterone was used as marker substrate, and generation of the 6β-hydroxy metabolite was monitored by high performance liquid chromatography coupled with diode array detector. IC50 values, inhibition constants, and rates of inhibition were determined. IC50 values ranged between 0.6 and 11.4 µM. The strongest inhibitor was chrysin (IC50 0.6 µM, inhibition constant 0.6 µM, inhibition rate constant 0.065 min–1, inhibition efficacy 0.108 min–1 µM–1). Compared to other flavonoids analyzed, chrysin’s inhibitory effect can be attributed to the hydrophobic nonsubstituted B ring, as well as rigidity of the structure. When foods rich in chrysin are consumed, e.g. honey and propolis, chrysin can cause food-drug interactions. Further in vitro studies are needed to determine the reactive intermediate responsible for inactivation of cytochrome P450 3A4 enzyme, as well as in vivo studies to determine possible clinical significance of this inhibition.
Biological actions of drug solvents ČULO, FILIP; ĆAVAR, IVAN; KELAVA, TOMISLAV
Periodicum biologorum,
11/2011, Letnik:
113, Številka:
3
Journal Article
Odprti dostop
Many biologic agents are weakly soluble in water. Therefore, they should be dissolved in organic lipophilic solvents (vehicles). A drug vehicle is a substance of no therapeutic value that is used to ...convey an active biological agent to the site of its action. Ideally, it should be biocompatible, 100% reliable, with no biological effect per se. However, presently used vehicles have pleiotropic effects, which are often unknown to researchers, and often cause misleading conclusions. In this review we summarize data on biological effects
of the three most commonly used lipophilic drug vehicles dimethylsulfoxide (DMSO), propylene glycol (PG) and ethanol. Besides in experimental models, the data, where available, are shown on effects of solvents in therapeutic use in humans. In conclusion, some recommendations are given on the use of drug solvents in experiments.
Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX) A2 is a powerful inducer of platelet ...aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP) is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT) in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX) B2 antibodies (anti-TXB2) and a selective inhibitor of thromboxane (TX) synthase, benzylimidazole (BZI), were significantly hepatoprotective, while a selective thromboxane receptor (TPR) antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.
Charles Bonnet syndrome (CBS) refers to visual hallucinations that occur in individuals with preserved cognitive functions associated with visual impairment.
This article reviews occurence of visual ...hallucinations in subjects with CBS by journals published in English in the Pubmed database in the period 1992-2018. Criteria for selection of appropriate papers were sufficient information and perspicuous view on pathogenesis, epidemiology, clinical presentation and treatment possibilities of CBS.
Most commonly, visual hallucinations in patients with CBS are complex, repetitive and stereotyped. Such individuals have preserved insight that those percepts are not real, and there is an absence of secondary explanatory delusions and hallucinations within other modalities. Seeing as the aforementioned percepts do not share all the characteristics of hallucinations, it remains unresolved how they should be referred to. Terms as release hallucinations, one that is reflecting its underlying pathogenesis, or confabulatory hallucinatory experiences have been proposed. Moreover, CBS has also been referred to as phantom vision syndrome and may occur in any ophthalmological disease. It is not particularly connected with loss of function along any level of the visual pathway. Although this syndrome is mostly associated with age-related macular degeneration, glaucoma and cataract, it could be related to almost any other ophthalmological conditions. The incidence of CBS alongside with mostly other ocular pathology is rising as population is ageing.
Nonetheless, CBS remains commonly underreported, under recognized and/or misrecognized. Albeit the treatment recommendations and guidelines are not yet fully established, it is important to raise awareness of this specific and distinct condition, which inevitably implicates many differential diagnostic deliberations.
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